Drug Resistance In Colorectal Cancer Research Articles

A novel Senescence-Based prognostic model unveils tumor interactions and drug resistance in colorectal cancer

BackgroundIn China, CRC incidence is escalating. The main hurdles are heterogeneity and drug resistance. This research delves into cellular senescence in CRC, aiming to devise a prognostic model and pinpoint mechanisms impacting drug resistance. MethodsMendelian randomization (MR) analysis confirmed the association between CRC and cellular aging. The Cancer Genome Atlas (TCGA)-CRC data served as the training set, with GSE38832 and GSE39582 as validation sets. Various bioinformatics methods were employed to construct and validate a risk model. CRC cells with NADPH Oxidase 4 (NOX4) knockout were generated using CRISPR-Cas9 technology. Protein blotting and colony formation assays elucidated the role of NOX4 in CRC cell aging and drug resistance. ResultsA prognostic model, derived from dataset analysis, uncovered a link between high-risk groups and cancer progression. Notable differences in the tumor microenvironment were observed between risk groups. Finally, NOX4 was found to be linked with aging and drug resistance in CRC. ConclusionThis research presents a novel senescence-based CRC prognosis model. It identifies NOX4′s role in CRC drug resistance, suggesting it is a potential treatment target.

Fe-MOF nanoplatform: Specifically overcoming oxaliplatin resistance in colorectal cancer through multifaceted pathways

Oxaliplatin (OXA) is a widely used chemotherapy drug for advanced colorectal cancer (CRC), yet resistance frequently and rapidly develops in patients. Here, we explored a Fe-based metal-organic framework (Fe-MOF) as a nanoplatform to simultaneously deliver OXA and a nitric oxide (NO) donor, specifically l-Arginine (L-Arg). The aim was to overcome OXA resistance in CRC cells, thereby enhancing the anticancer efficacy against drug-resistant CRC. Due to the abundant glutathione (GSH) in tumor tissue, Fe3+ in Fe-MOF undergoes reduction to Fe2+, causing the collapse of Fe-MOF structure and the subsequent release of OXA and L-Arg. This process is accompanied by GSH depletion, amplifying the effectiveness of OXA against drug-resistant CRC. Fe2+ further reacts with overexpressed H2O2 to generate •OH, inducing direct cell apoptosis and subsequently reacting with L-Arg to rapidly produce NO. NO plays multifaceted roles in the anti-CRC effect, reversing drug resistance in CRC cells through multiple pathways, inducing apoptosis of CRC cells to initiate gas therapy, and reacting with •OH to generate highly toxic reactive nitrogen species for cancer cell destruction. This synergistic strategy effectively addresses the challenge of drug resistance in CRC, offering a promising avenue for enhancing the clinical effectiveness of OXA in cases resistant to conventional treatment.

Abstract 374: Hypoxia-induced mitochondrial glutathione transporter expression causes drug resistance in colorectal cancer

Abstract Colorectal cancer (CRC) is the third most common type of cancer worldwide, with higher incidence and mortality rates. In order to adapt stress conditions during cancer progression, the cancer cells will be subject to metabolism reprogramming to increase energy production and remove hazardous substances. One of the important organelles, mitochondria is responsible for cellular ATP production, ion homeostasis, and several metabolic pathways. Therefore, mitochondria require a series of transporters called solute carrier family 25 (SLC25) to transport metabolites crossing the mitochondrial inner membrane, and dysregulation of those transporters causes abnormal cell morphology and diseases. In this study, members of the SLC25 family were analyzed in CRC via bioinformatics analysis, and a mitochondrial glutathione transporter was identified to overexpress in several public datasets of CRC and our own clinical specimens. In addition, its role has not been reported in any disease, including cancer. To systemically analyze the underlying mechanism causing overexpression of glutathione transporter during CRC progression, several stress conditions had been applied to colon cancer cells. However, only hypoxia was identified to induce its protein expression but not mRNA expression. Since a previous study reported that glutathione deprivation induced its protein expression, hypoxia didn’t alter the abundance of glutathione level suggesting that another glutathione-independent regulatory mechanism might be involve it. Interestingly, our findings revealed that hypoxia-induced glutathione transporter protein expression was mediated through the activation of internal ribosome binding site-mediated translation under hypoxia. To identify the potential role of glutathione transporter during colon cancer progression, its mitochondrial metabolite profiles from knockout cells of previous studies were further analyzed and identified that the changes of metabolites were associated with the urea cycle which had been reported to be associated with the sensitivity of oxaliplatin and 5-fluorouracil (5-FU) in cancer treatment. Importantly, our results showed that hypoxia-attenuated those chemotherapeutic effects were abolished by loss of glutathione transporter in colon cancer cells, indicating its crucial role in hypoxia-induced drug resistance. In conclusion, our study shows that glutathione transporter increased by hypoxia might lead to drug resistance of cancer therapy in colon cancer. Citation Format: Chin-Chun Lin. Hypoxia-induced mitochondrial glutathione transporter expression causes drug resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 374.

Abstract 306: The role of exosomal UBE2R2 in colorectal cancer drug resistance

Abstract Background: Ctherapy resistance has been a major barrier against successful theratment. Exosome (EV), an important intercellular communication mediator, participates in a highly and complex network that drug resistance of cancer cells. EV has been reported to be able to transfer drug resistance from drug-resistant tumor cells to adjacent drug-sensitive cells. We identified a novel target, UBE2R2, based on our previous exosome proteomics analysis of resistant colorectal cancer cell lines. The main goal of this study is to validate the underlying mechanisms leading to chemotherapy resistance. Methods: We isolated EV from drug resistant cancer cell lines including coloractal cancer cell lines (HCT116-OXAR, DLD-1 OXA-R, DLD-1-OXA-R/SN38) its parental cell lines (HCT116, DLD-1) using the ExoLutE isolation kits based on a combination of multiple isolation techniques. Based on the existing data (proteomic analysis), we conducted experiments to elucidate the functions and mechanisms involved in cancer resistance of the identified UBE2R2. Cell viability assay and invasion asaay were performed to assess the effects of EVs drived from drug resistance colorectal cells on oxaliplatin and irinotecan resistance. In addition, cells transfected with siControl and siUBE2R2 were treated with oxaliplatin to access the relative UBE2R2 drug resistance effect. To explore the related mechanisms, we performed real time PCR and western blot to identify the UBE2R2-SMYD3-P53 pathway, and FACS analysis to confirm apoptosis. Additionally, TMA samples were utilized to confirm resistance according to patient stage, and UBE2R2 expression was validated by immunohistological methods. Results: UBE2R2, which is involved in ubiquitination, was most prominently expressed in resistant cell lines compared to controls in our previous proteomic analysis. Based on these results, we found that cell lines treated with exosomes which were derived from resistant cell lines showed lower sensitivity to the drug. Notably, treatment of resistant cell lines with siUBE2R2 resulted in increased sensitivity, confirming the involvement of UBE2R2 in resistance. As a possible mechanism in which UBE2R2 may be involved, western analysis targeting the SMYD-P53 mechanism showed that the combination of UBE2R2-SMYD3-p53 promoted the ubiquitination and degradation of p53. Analyzed using TMA patient samples, we found that the expression of UBE2R2 increased towards more advenced stage. Conclusion: Our results suggest a novel mechanism of chemotherapy resistance may be associated with UBE2R2. Exosome (including UBE2R2) which was drived from drug resistance cells may induce oxaliplatin and irinotecan resistance in parental colorectal cells via regulation of SMYD3-UBE2R2-P53 signaling pathway, which will be useful for investigating a potential clinical target in prediction drug resistance. Citation Format: Chi Hoon Maeng, Minji Choi. The role of exosomal UBE2R2 in colorectal cancer drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 306.

PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment.

In the last decade, pathway-specific targeted therapy has revolutionized colorectal cancer (CRC) treatment strategies. This type of therapy targets a tumor-vulnerable spot formed primarily due to an alteration in an oncogene and/or a tumor suppressor gene. However, tumor heterogeneity in CRC frequently results in treatment resistance, underscoring the need to understand the molecular mechanisms involved in CRC for the development of novel targeted therapies. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) signaling pathway axis is a major pathway altered in CRC. The aberrant activation of this pathway is associated with CRC initiation, progression, and metastasis and is critical for the development of drug resistance in CRC. Several drugs target PI3K/Akt/mTOR in clinical trials, alone or in combination, for the treatment of CRC. This review aims to provide an overview of the role of the PI3K/Akt/mTOR signaling pathway axis in driving CRC, existing PI3K/Akt/mTOR-targeted agents against CRC, their limitations, and future trends.

The potential therapeutic effect of melatonin in oxaliplatin combination therapy against chemoresistant colorectal cancer cells.

Oxaliplatin is one of the main therapeutics in colorectal cancer (CRC) chemotherapy. However, in light of multidrug resistance (MDR) phenotype development, the efficacy of oxaliplatin has decreased. This study aimed to assess the potential therapeutic effect of melatonin in oxaliplatin combination therapy for drug-resistant colorectal cancer cells. Initially, the oxaliplatin-resistant cell line was created of LS174T (LS174T/DR) by using the oxaliplatin IC50 concentration and resting cycles. MTT assays and flow cytometry were applied for assessing cell viability and apoptotic cells. The mRNA expression level of Bax, Bcl2, MT1, MT2, and ABCB1 as well as protein levels of ABCB1, Bcl2, BAX were measured by the qRT-PCR and western blot techniques respectively. P-gp activity was assessed by Rho123 staining. The IC50 concentration of oxaliplatin in resistant cells was increased from 500.7 ± 0.2 nM to 7119 ± 0.1 nM. Bcl2, MT1, MT2, and ABCB1 mRNA plus protein expression levels of Bcl2 and ABCB1 were significantly reduced in resistant cells, along with a marked increase in Bax mRNA and protein levels compared to parental cells. Rho 123 staining revealed a marked reduction in P-gp activities in the combination-treated group compared to the oxaliplatin-treated group. The results of cytotoxicity assays, MTT, and flow cytometry revealed that the combination of melatonin and oxaliplatin exerts synergistic effects on induction of oxaliplatin's cytotoxicity in CRC. Our research suggests that combining the treatments of melatonin and oxaliplatin may be considered as a new approach to overcoming oxaliplatin resistance in CRC patients.

Development and Nanoparticle-Mediated Delivery of Novel MDM2/MDM4 Heterodimer Peptide Inhibitors to Enhance 5-Fluorouracil Nucleolar Stress in Colorectal Cancer Cells.

Colorectal cancer (CRC) often involves wild-type p53 inactivation by MDM2 and MDM4 overexpression, promoting tumor progression and resistance to 5-fluoruracil (5-FU). Disrupting the MDM2/4 heterodimer can proficiently reactivate p53, sensitizing cancer cells to 5-FU. Herein, we developed 16 peptides based on Pep3 (1), the only known peptide acting through this mechanism. The new peptides, notably 3 and 9, showed lower IC50 values than 1. When incorporated into tumor-targeted biodegradable nanoparticles, these exhibited cytotoxicity against three different CRC cell lines. Notably, NPs/9 caused a significant increase in p53 levels associated with a strong increment of its main downstream target p21 inducing apoptosis. Also, the combined treatment of 9 with 5-FU caused the activation of nucleolar stress and a synergic apoptotic effect. Hence, the co-delivery of MDM2/4 heterodimer disruptors with 5-FU through nanoparticles might be a promising strategy to overcome drug resistance in CRC.

Multi drug resistance in Colorectal Cancer- approaches to overcome, advancements and future success

A significant obstacle to treating cancer is multidrug resistance (MDR), which is the capacity of cancerous cells to develop resistance to both traditional and cutting-edge chemotherapeutic treatments. Following the initial discovery that cellular pumps reliant on ATP were the root of chemotherapy resistance, more research has revealed the involvement of additional mechanisms, including increased drug metabolism, reduced drug entry, and compromised apoptotic pathways. Numerous projects have focused on MDR, and innumerable research has been conducted to better understand MDR and develop methods to mitigate its consequences. Multidrug resistance (MDR) is a key challenge in treating cancer. 90% of cancer-related fatalities are brought on by tumor metastasis and recurrence, which is possible with MDR. Drug resistance in cancerous cells is influenced by diverse internal and extrinsic variables, including genetic and epigenetic changes, drug efflux systems, DNA repair mechanisms, apoptosis, and autophagy. In this review paper, we list the potential hazards associated with cancer therapy in general, primarily multidrug resistance developing a theory for colorectal cancer in particular. We discussed the unique instance of multidrug resistance in colorectal cancer in malignancies generally and 5-fluorouracil, curcumin, and lipids as viable therapy options for the condition. The use of nanotechnology (mainly nanoparticles) has facilitated better in vitro as well as in vivo efficacy during preclinical phases, summarized below, allowing for a more thorough investigation of colorectal cancers and pancreatic carcinomas with their translation to following clinical trials.

Remotely Controllable Supramolecular Nanomedicine for Drug-Resistant Colorectal Cancer Therapy Caused by Fusobacterium nucleatum.

Fusobacterium nucleatum (Fn) existing in the community of colorectal cancer (CRC) promotes CRC progression and causes chemotherapy resistance. Despite great efforts that have been made to overcome Fn-induced chemotherapy resistance by co-delivering antibacterial agents and chemotherapeutic drugs, increasing the drug-loading capacity and enabling controlled release of drugs remain challenging. In this study, a novel supramolecular upconversion nanoparticle (SUNP) is constructed by incorporating a positively charged polymer (PAMAM-LA-CD) with Fn inhibition capacity, a negatively charged platinum (IV) oxaliplatin prodrug (OXA-COOH), upconversion nanoparticle (UCNPs) and polyethylene glycol-azobenzene (PEG-Azo) to enhance drug-loading and enable on-demand drug release for drug-resistant CRC treatment. SUNPs exhibit high drug-loading capacity (30.8%) and good structural stability under normal physiological conditions, while disassembled upon exogenous NIR excitation and endogenous azo reductase in the CRC microenvironment to trigger drug release. In vitro and in vivo studies demonstrate that SUNPs presented good biocompatibility and robust performance to overcome chemoresistance, thereby significantly inhibiting Fn-infected cancer cell proliferation. This study leverages multiple dynamic chemical designs to integrate both advantages of drug loading and release in a single system, which provides a promising candidate for precision therapy of bacterial-related drug-resistant cancers.

RPF2 mediates the CARM1‑MYCN axis to promote chemotherapy resistance in colorectal cancer cells.

Ribosome production factor 2 homolog (RPF2) plays an important role in the life processes of ribosomal biogenesis; however, the function and mechanism of RPF2 in tumors are unclear. The present study demonstrated that RPF2 expression is involved in chemoresistance in colorectal cancer (CRC) cells. The current study demonstrated that upregulation of RPF2 expression in CRC promoted resistance to chemotherapeutic agents in CRC cells, whereas knockdown of RPF2 leads to increased sensitivity of CRC to chemotherapy. In addition, it was found that overexpression of RPF2 led to an increase in ATP‑binding cassette (ABC)B1 expression in CRC cells; accordingly, inhibition of RPF2 reduced the level of ABCB1 in CRC cells, thus suggesting that ABCB1 may be a downstream factor of RPF2 in the promotion of chemotherapy resistance to CRC. The results also suggested that the expression of N‑myc proto‑oncogene protein (MYCN), an upstream regulator of ABCB1, was affected by RPF2 in CRC cells. In addition, it was also found that the downstream protein coactivator‑associated arginine methyltransferase 1 (CARM1) of RPF2 existed in direct binding to MYCN and this interaction was regulated by RPF2. The above results suggested that RPF2 is probably regulated ABCB1 expression in CRC through the CARM1‑MYCN pathway, thereby promoting CRC drug resistance.

Harnessing Ferroptosis to Overcome Drug Resistance in Colorectal Cancer: Promising Therapeutic Approaches.

Drug resistance remains a significant challenge in the treatment of colorectal cancer (CRC). In recent years, the emerging field of ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation, has offered new insights and potential therapeutic strategies for overcoming drug resistance in CRC. This review examines the role of ferroptosis in CRC and its impact on drug resistance. It highlights the distinctive features and advantages of ferroptosis compared to other cell death pathways, such as apoptosis and necrosis. Furthermore, the review discusses current research advances in the field, including novel treatment approaches that target ferroptosis. These approaches involve the use of ferroptosis inducers, interventions in iron metabolism and lipid peroxidation, and combination therapies to enhance the efficacy of ferroptosis. The review also explores the potential of immunotherapy in modulating ferroptosis as a therapeutic strategy. Additionally, it evaluates the strengths and limitations of targeting ferroptosis, such as its selectivity, low side effects, and potential to overcome resistance, as well as challenges related to treatment specificity and drug development. Looking to the future, this review discusses the prospects of ferroptosis-based therapies in CRC, emphasizing the importance of further research to elucidate the interaction between ferroptosis and drug resistance. It proposes future directions for more effective treatment strategies, including the development of new therapeutic approaches, combination therapies, and integration with emerging fields such as precision medicine. In conclusion, harnessing ferroptosis represents a promising avenue for overcoming drug resistance in CRC. Continued research efforts in this field are crucial for optimizing therapeutic outcomes and providing hope for CRC patients.

Syndecan-2 modulates the YAP pathway in epithelial-to-mesenchymal transition-related migration, invasion, and drug resistance in colorectal cancer

Epithelial-to-mesenchymal transition (EMT) is associated with an invasive phenotype in colorectal cancer (CRC). Here, we examined the roles of YES-associated protein (YAP) and syndecan-2 (SDC2) in EMT-related progression, invasion, metastasis, and drug resistance in CRC. The expression levels of YAP and SDC2 in CRC patient tumor tissue were quantified by PCR and western blotting. EMT-associated characteristics were assessed using Transwell assays and immunohistochemistry. Co-immunoprecipitation, glutathione S-transferase pull-down, and luciferase reporter assays were used to assess interactions between YAP and SDC2. YAP was found to be highly expressed in tumor tissue from 13/16 CRC patients, while SDC2 was highly expressed in the tumor tissue of 12/16 CRC patients. Overexpression of YAP in colon cancer cells led to increased cell viability, invasion, migration, and oxaliplatin resistance demonstrating that YAP plays a role in EMT. In addition, overexpression of YAP led to decreased expression of the large tumor suppressor kinase 1 (LATS1) and mammalian sterile 20-like kinases (MST1/2). Decreased LATS1 expression was associated with increased levels of cell proliferation. Knockdown of YAP by shRNA interference led to decreased cell invasion, migration, and drug resistance in colon cancer cells and reduced tumorigenesis in a mouse xenograft model. Finally, we established that YAP interacted with SDC2, and demonstrated that SDC2 mediated the YAP pathway through the EMT-related factors BMP4, CTGF and FOXM1.

ENO2-derived phosphoenolpyruvate functions as an endogenous inhibitor of HDAC1 and confers resistance to antiangiogenic therapy.

Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we identify the glycolytic enzyme enolase 2 (ENO2) as a driver of resistance to antiangiogenic therapy in colorectal cancer (CRC) mouse models and human participants. ENO2 overexpression induces neuroendocrine differentiation, promotes malignant behaviour in CRC and desensitizes CRC to antiangiogenic drugs. Mechanistically, the ENO2-derived metabolite phosphoenolpyruvate (PEP) selectively inhibits histone deacetylase 1 (HDAC1) activity, which increases the acetylation of β-catenin and activates the β-catenin pathway in CRC. Inhibition of ENO2 with enolase inhibitors AP-III-a4 or POMHEX synergizes the efficacy of antiangiogenic drugs in vitro and in mice bearing drug-resistant CRC xenograft tumours. Together, our findings reveal that ENO2 constitutes a useful predictive biomarker and therapeutic target for resistance to antiangiogenic therapy in CRC, and uncover a previously undefined and metabolism-independent role of PEP in regulating resistance to antiangiogenic therapy by functioning as an endogenous HDAC1 inhibitor.

Novel insights on perils and promises of miRNA in understanding colon cancer metastasis and progression.

Colorectal cancer (CRC) is the third highest frequent malignancy and ultimate critical source of cancer-associated mortality around the world. Regardless of latest advances in molecular and surgical targeted medicines that have increased remedial effects in CRC patients, the 5-year mortality rate for CRC patients remains dismally low. Evidence suggests that microRNAs (miRNAs) execute an essential part in the development and spread of CRC. The miRNAs are a type of short non-coding RNA that exhibited to control the appearance of tumor suppressor genes and oncogenes. miRNA expression profiling is already being utilized in clinical practice as analytical and prognostic biomarkers to evaluate cancer patients' tumor genesis, advancement, and counteraction to drugs. By modulating their target genes, dysregulated miRNAs are linked to malignant characteristics (e.g., improved proliferative and invasive capabilities, cell cycle aberration, evasion of apoptosis, and promotion of angiogenesis). This review presents an updated summary of circulatory miRNAs, tumor-suppressive and oncogenic miRNAs, and the potential reasons for dysregulated miRNAs in CRC. Further we will explore the critical role of miRNAs in CRC drug resistance.

Exploring the Role of Circulating Cell-Free RNA in the Development of Colorectal Cancer.

Circulating tumor RNA (ctRNA) has recently emerged as a novel and attractive liquid biomarker. CtRNA is capable of providing important information about the expression of a variety of target genes noninvasively, without the need for biopsies, through the use of circulating RNA sequencing. The overexpression of cancer-specific transcripts increases the tumor-derived RNA signal, which overcomes limitations due to low quantities of circulating tumor DNA (ctDNA). The purpose of this work is to present an up-to-date review of current knowledge regarding ctRNAs and their status as biomarkers to address the diagnosis, prognosis, prediction, and drug resistance of colorectal cancer. The final section of the article discusses the practical aspects involved in analyzing plasma ctRNA, including storage and isolation, detection technologies, and their limitations in clinical applications.

CX43 down-regulation promotes cell aggressiveness and 5-fluorouracil-resistance by attenuating cell stiffness in colorectal carcinoma

ABSTRACT Chemotherapy is one of the most commonly treatments of advanced colorectal cancer (CRC). However, the drug resistant following chemotherapeutic treatment is a significant challenge in the clinical management of CRC. Therefore, understanding the resistance mechanisms and developing new strategies for enhancing the sensitivity are urgently needed to improve CRC outcome. Connexins contribute to the formation of gap junctions among neighboring cells and then advance gap junctional intercellular communication (GJIC) for transportation of ions and small molecules. Although the drug resistance resulted from GJIC dysfunctional by aberrant expression of connexins is relatively well understood, the underlying mechanisms of mechanical stiffness mediated by connexin responsible for chemoresistance are largely unknown in CRC. Here, we demonstrated that connexin 43 (CX43) expression was downregulated in CRC and that loss of CX43 expression was positively correlated with metastasis and poor prognosis of CRC patients. The CX43 overexpressing suppressed CRC progression and increased the sensitivity to 5-fluorouracil (5-FU) via enhanced GJIC in vitro and in vivo. Moreover, we also highlight that the downregulation of CX43 in CRC increases the stemness of cells via reducing the cell stiffness, thus promoting the drug resistance. Our results further suggest that both effects, that is changes in the mechanical stiffness of the cell and GJIC mediated by CX43 deregulated, are closely related to drug resistance in CRC, which indicating CX43 as a target against cancer growth and chemoresistance in CRC.

Scutellaria baicalensis enhances 5-fluorouracil-based chemotherapy via inhibition of proliferative signaling pathways

Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and normal human colon epithelial cells. In vivo animal models were used to document the antitumor activity of HQ and baicalin. The mechanism of growth inhibitory activity of HQ is due to inhibition of proliferative signaling pathways including the CDK-RB pathway. In addition, HQ enhanced the antitumor effects of 5-FU and capecitabine in vivo. Furthermore, we identified baicalin as an active component of HQ. The combination of baicalin and 5-FU demonstrated synergistic activity against 5-FU-resistant RKO-R10 cells. The combination significantly inhibited in vivo tumor growth greater than each treatment alone. RPPA results showed that the signaling pathway alterations in CRC cells were similar following HQ and baicalin treatment. Together, these results indicate that HQ and its component baicalin enhance the effect of 5-fluorouracil-based chemotherapy via inhibition of CDK-RB pathway. These findings may provide the rational basis for developing agents that can overcome the development of cellular drug resistance.9Q3bw5kPrTjBvtYuEHSNmaVideo

Sanguisorba officinalis L. enhances the 5-fluorouracil sensitivity and overcomes chemoresistance in 5-fluorouracil-resistant colorectal cancer cells via Ras/MEK/ERK and PI3K/Akt pathways

Sanguisorba officinalis L., a traditional Chinese medicine (TCM) called DiYu (DY) in China, has a strong tradition of utilization as a scorching, blood-cooling, and hemostatic medication, and was used for cancer prevention and treatment due to its potential immune-enhancing and hematological toxicity-reducing effects. Previous studies have reported significant effects of DY on cancers including colorectal cancer (CRC), which is one of the most common malignancies worldwide. The first-line cure 5-fluorouracil (5-FU) plays decisive commerce in the sedative of CRC as a clinically available chemotherapeutic agent. One of the primary causes of cancer treatment failure is the acquisition of chemotherapy drug resistance. In order to successfully combat the emergence of chemoresistance, it is essential to identify herbs or traditional Chinese medicine that have adjuvant therapeutic effects on CRC. Therefore, this study aimed to determine whether DY could improve the sensitivity, conquer the chemoresistance of 5-FU-resistant CRC cells, and investigate its intrinsic mechanism. Materials and methodsMTT, Hoechst 33258 staining, and flow cytometry assays were used to determine the anticancer activity of DY alone or in combination with 5-FU against 5-FU-resistant CRC cells (RKO-R and HCT15-R) and wound healing assays were conducted to detect cell migration. Transcriptomic techniques were carried out to explore the effect and mechanism of DY on drug-resistant CRC cells. Western Blot and RT q-PCR assays were performed to validate the mechanism by which DY overcomes drug-resistant CRC cells. ResultsThese results indicated that DY alone or in combination with 5-FU significantly inhibited the proliferation and the migration of resistant CRC cells, and potentiated the susceptibility of 5-FU to drug-resistant CRC cells. GO and KEGG enrichment analysis showed that the mechanisms of drug resistance in CRC cells and DY against drug-resistant CRC cells highly overlapped, involved in the modulation of biological processes such as cell migration, positive regulation of protein binding and cytoskeleton, and MAPK (Ras-ERK-MEK), PI3K/Akt, and other signaling pathways. Moreover, DY can mediate the expression of p-R-Ras, p-ERK1/2, p-MEK1/2, p-PI3K, p-AKT, HIF-1A and VEGFA proteins. In addition, DY significantly suppressed the expression of AKT3, NEDD9, BMI-1, and CXCL1 genes in resistant CRC cells. ConclusionIn conclusion, DY could inhibit the proliferation and migration of 5-FU-resistant cells and strengthen the sensitivity of 5-FU to CRC-resistant cells. Furthermore, DY may prevail over chemoresistance through the Ras/MEK/ERK and PI3K/Akt pathways. These findings imply that DY may be a potential drug for clinical treatment or adjuvant treatment of drug-resistant CRC.

Knockdown of hnRNPAB reduces the stem cell properties and enhances the chemosensitivity of human colorectal cancer stem cells.

Heterogeneous ribonucleoproteinAB (hnRNPAB) is one of the main members of the nuclear heterogeneous ribonucleoprotein family and plays a crucial role in the occurrence and development of tumours. A previous study by the authors demonstrated that hnRNPAB was highly expressed in colorectal cancer tissues and was closely associated with a poor prognosis of patients. However, the contribution of hnRNPAB to the tumorigenesis and drug resistance of colorectal cancer (CRC) stem cells (CSCs) remains elusive. The aim of the present study was thus to examine whether hnRNPAB can enhance the characteristics of colorectal CSCs and chemotherapeutic drug resistance by altering the cell cycle and the apoptosis of colorectal CSCs. The results revealed that the expression of hnRNPAB in colorectal CSCs was increased compared with that in their parental cells. The knockdown of hnRNPAB reduced the sphere formation of and the levels of CSC markers in colorectal CSCs, enhanced sensitivity to 5‑fluorouracil and oxaliplatin chemotherapy and increased apoptosis. Taken together, these data indicate the role of hnRNPAB in maintaining CSC properties and provide a novel therapeutic target for the treatment of CRC and particularly, drug resistance.

TYRO3 promotes tumorigenesis and drug resistance in colorectal cancer by enhancing the epithelial-mesenchymal transition process

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Although considerable advances in CRC treatment have been achieved, effective treatment improvement has hit a bottleneck. This study demonstrated that TYRO3 expression was aberrantly increased in CRC tissues with prognosis association. The prediction model of prognosis for CRC patients was constructed based on TYRO3 expression. The model suggested that the TYRO3 level is crucial to the final prediction results. We observed that knockdown TYRO3 expression could inhibit the proliferation and migration ability and reverse the drug resistance by constructing drug-resistant CRC cell lines. In vivo experiments also confirmed this conclusion. Thus, targeting TYRO3 combined with 5-Fu treatment could provide a better therapeutic effect. Additionally, TYRO3 could inhibit the EMT process by down-regulating ENO1, which may be achieved by interfering with energy metabolism in cancer cells. Therefore, the current study provides a theoretical basis for TYRO3 in drug-resistance of CRC cells and highlights a new strategy for CRC-targeted therapy.