Tumor Chemotherapy Resistance Research Articles

Imaging of carboxylesterase 2 expression changes in colitis and colon cancer chemotherapy via a fluorescent probe

Colitis is one of the important etiologies of colon cancer, but the diagnosis of early colitis and colon cancer is still a difficult problem, so it is important to use reasonable methods to achieve the diagnosis of early colitis and colon cancer. Carboxylesterase 2 (CES2) is momentous in the development of colon disease and can be used as an indicator to distinguish colitis from colon cancer. CES2 is expressed differently in colitis and colon cancer, so it has the potential to distinguish colitis from colon cancer by detecting the difference in CES2 expression. We designed a fluorescent probe Bcy-CES2 for imaging CES2 in cells and in vivo and evaluating the differences in CES2 levels in colon disease. Probe Bcy-CES2 shows good potential for in situ real-time monitoring of endogenous CES2. In addition, we found that the combination of CES2 inhibitor BNPP and cisplatin can reduce tumor chemotherapy resistance, and CES2 levels may become a new index for early diagnosis and prognosis of colon cancer.

Alpha-hederin reprograms multi-miRNAs activity and overcome small extracellular vesicles-mediated paclitaxel resistance in NSCLC.

Background: Small extracellular vesicles (sEVs) mediate intercellular communication in the tumor microenvironment (TME) and contribute to the malignant transformation of tumors, including unrestricted growth, metastasis, or therapeutic resistance. However, there is a lack of agents targeting sEVs to overcome or reverse tumor chemotherapy resistance through sEVs-mediated TME reprogramming. Methods: The paclitaxel (PTX)-resistant A549T cell line was used to explore the inhibitory effect of alpha-hederin on impeding the transmission of chemoresistance in non-small cell lung cancer (NSCLC) through the small extracellular vesicles (sEVs) pathway. This investigation utilized the CCK-8 assay and flow cytometry. Transcriptomics, Western blot, oil red O staining, and targeted metabolomics were utilized to evaluate the impact of alpha-hederin on the expression of signaling pathways associated with chemoresistance transmission in NSCLC cells before and after treatment. In vivo molecular imaging and immunohistochemistry were conducted to assess how alpha-hederin influences the transmission of chemoresistance through the sEVs pathway. RT-PCR was employed to examine the expression of miRNA and lncRNA in response to alpha-hederin treatment. Results: The resistance to PTX chemotherapy in A549T cells was overcome by alpha-hederin through its dependence on sEV secretion. However, the effectiveness of alpha-hederin was compromised when vesicle secretion was blocked by the GW4869 inhibitor. Transcriptomic analysis for 463 upregulated genes in recipient cells exposed to A549T-derived sEVs revealed that these sEVs enhanced TGFβ signaling and unsaturated fatty acid synthesis pathways. Alpha-hederin inhibited 15 types of unsaturated fatty acid synthesis by reducing the signaling activity of the sEVs-mediated TGFβ/SMAD2 pathway. Further, we observed that alpha-hederin promoted the production of three microRNAs (miRNAs, including miR-21-5p, miR-23a-3p, and miR-125b-5p) and the sorting to sEVs in A549T cells. These miRNAs targeted the TGFβ/SMADs signaling activity in sEVs-recipient cells and sensitized them to the PTX therapy. Conclusion: Our finding demonstrated that alpha-hederin could sensitize PTX-resistant NSCLC cells by sEV-mediated multiple miRNAs accumulation, and inhibiting TGFβ/SMAD2 pathways in recipient cells.

MiR-125b-5p-MAPK1-C/EBPα feedback loop regulates all-trans retinoic acid resistance in acute promyelocytic leukemia

BackgroundVarious studies have highlighted the significance of miR-125b-5p in tumour chemotherapy resistance; However, whether miR-125b-5p is associated with all-trans retinoic acid (ATRA) resistance in acute promyelocytic leukemia (APL) has not been reported. MethodsDrug-resistance-related factors in APL were predicted using the DRESIS database. The expression levels of miR-125b-5p in ATRA-sensitive and ATRA-resistant APL cells were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A nitrotetrazolium blue (NBT) reduction assay and flow cytometry (FCM) were used to detect the effect of miR-125b-5p on ATRA resistance in APL cells. An APL xenograft tumour mouse model was established to determine the effect of miR-125b-5p on ATRA resistance. A dual-luciferase gene reporter assay, qRT-PCR, and western blotting verified the regulation by miR-125b-5p of its target gene, MAPK1, and the MAPK1 downstream factor, C/EBPα. An NBT reduction assay and FCM were used to detect the effect of C/EBPα on ATRA resistance in APL cells. Western blotting and qRT-PCR were used to assess the regulation of miR-125b-5p and MAPK1 by C/EBPα. ResultsmiR-125b-5p expression levels were dramatically increased in ATRA-resistant APL cells. Both in vitro and in vivo experiments revealed that miR-125b-5p overexpression enhanced ATRA resistance in APL. miR-125b-5p promoted ATRA resistance by sponging MAPK1. C/EBPα was negatively regulated by miR-125b-5p, which in addition, regulated ATRA resistance in APL cells. C/EBPα also regulated the miR-125b-5p-MAPK1 axis. ConclusionThe findings of this study indicate that the miR-125b-5p-MAPK1-C/EBPα feedback loop regulated ATRA resistance in APL. Thus, miR-125b-5p may be a promising target for treating ATRA resistance in APL.

Interleukin-10 increases macrophage-mediated chemotherapy resistance via FABP5 signaling in multiple myeloma

Macrophages (MΦs) protect multiple myeloma (MM) cells from chemotherapy-induced apoptosis, and interleukin-10 (IL-10) is frequently elevated in the MM microenvironment. However, the role of IL-10 in MΦ-induced tumor chemotherapy resistance has not yet been clarified. In the present study, bone marrow-derived MΦs were treated with IL-10 (IL10-MΦs), and IL10-MΦ-induced MM chemotherapy resistance was evaluated. IL-10 promoted MΦ-mediated resistance to MM chemotherapy. In addition, IL-10 treatment increased lipid accumulation and fatty acid β-oxidation in MΦs. Mechanistically, IL-10 increased fatty acid binding protein 5 (FABP5) expression in MΦs, and targeting FABP5 decreased MM chemotherapy resistance induced by IL10-MΦs in vitro and enhanced chemotherapeutic efficacy in vivo. Inhibition of FABP5 decreased the expression of Carnitine Palmitoyltransferase 1A (CPT1A) in IL10-MΦs. In addition, inhibition of CPT1A in IL10-MΦs decreased IL10-MΦ-mediated MM chemotherapy resistance. Peroxisome proliferator-activated receptor γ (PPARγ) is upstream of FABP5 signaling. Inhibition of PPARγ in IL10-MΦs decreased IL10-MΦ-mediated MM chemotherapy resistance in vitro. Collectively, our work indicates that IL-10 enhances MΦ-mediated MM chemotherapy resistance via FABP5 signaling and targeting FABP5 has potentially important clinical implications.

ZLDI-8 suppresses angiogenesis and vasculogenic mimicry in drug-resistant NSCLC in vitro and in vivo

AimsThe chemotherapy drugs for NSCLC often face the consequences of treatment failure due to acquired drug resistance. Tumor chemotherapy resistance is often accompanied by angiogenesis. Here, we aimed to investigate the effect and underlying mechanisms of ADAM-17 inhibitor ZLDI-8 we found before on angiogenesis and vasculogenic mimicry(VM) in drug-resistant NSCLC. Main methodsThe tube formation assay was used to evaluate angiogenesis and VM. Migration and invasion were assessed with transwell assays in the co-culture condition. To explore the underlying mechanisms of how ZLDI-8 inhibited tubes formation, ELISA assay and western blot assay were preformed. The effects of ZLDI-8 on angiogenesis in vivo were investigated in Matrigel plug, CAM and Rat aortic ring assays. Key findingsIn the present study, ZLDI-8 significantly inhibited the tube formation of human umbilical vein endothelial cells (HUVECs) in either normal medium or in tumor supernatants. Furthermore, ZLDI-8 also inhibited VM tubes formation of A549/Taxol cells. In the co-culture assay, the interaction between lung cancer cells and HUVECs promotes increased cell migration and invasion, while ZLDI-8 eliminates this promotion. Moreover, the VEGF secretion were decreased by ZLDI-8 and the expression of Notch1, Dll4, HIF1α and VEGF were inhibited by ZLDI-8. In addition, ZLDI-8 can inhibit blood vessel formation in the Matrigel plug, CAM and Rat aortic ring assays. SignificanceZLDI-8 inhibits angiogenesis and VM in drug-resistant NSCLC through suppressing Notch1-HIF1α-VEGF signaling pathway. This study lays the foundation for the discovery of drugs that inhibit angiogenesis and VM in drug resistant NSCLC.

The role of tumor microenvironment reprogramming in primary liver cancer chemotherapy resistance.

Primary liver cancer (PLC), including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), and other rare tumours, is the second leading cause of cancer-related mortality. It has been a major contributor to the cancer burden worldwide. Of all primary liver cancer, HCC is the most common type. Over the past few decades, chemotherapy, immunotherapy and other therapies have been identified as applicable to the treatment of HCC. However, evidence suggests that chemotherapy resistance is associated with higher mortality rates in liver cancer. The tumour microenvironment (TME), which includes molecular, cellular, extracellular matrix(ECM), and vascular signalling pathways, is a complex ecosystem. It is now increasingly recognized that the tumour microenvironment plays a pivotal role in PLC prognosis, progression and treatment response. Cancer cells reprogram the tumour microenvironment to develop resistance to chemotherapy drugs distinct from normal differentiated tissues. Chemotherapy resistance mechanisms are reshaped during TME reprogramming. For this reason, TME reprogramming can provide a powerful tool to understand better both cancer-fate processes and regenerative, with the potential to develop a new treatment. This review discusses the recent progress of tumour drug resistance, particularly tumour microenvironment reprogramming in tumour chemotherapy resistance, and focuses on its potential application prospects.

MiR-30a-5p/CHD1 axis enhances cisplatin sensitivity of ovarian cancer cells via inactivating the Wnt/β-catenin pathway.

Oovarian cancer is a common lethal gynecological malignancy with a high occurrence and dismal prognosis on account of its drug resistance. MicroRNAs (miRNAs) are widely involved in the chemotherapy resistance of tumors, including miR-30a-5p. Herein, we probed the functional role and molecular mechanism of miR-30a-5p in the chemoresistance of ovarian cancer. We enrolled 48 ovarian cancer patients in this study. Statistical analysis and a series of experiments including quantitative reverse transcription polymerase chain reaction, western blot, methyl thiazolyl tetrazolium assay, colony formation assay, flow cytometry analysis, Transwell assay, luciferase reporter assay, RNA pull-down assay and TOP/FOP flash assay were explored in the study. Animal experiments were performed to verify the role of miR-30a-5p in vivo . In our study, miR-30a-5p showed a prominently low level in ovarian cancer tissues and cells. Importantly, its expression in cisplatin-resistant cell lines was more downregulated than in cisplatin-sensitive ones. Additionally, miR-30a-5p overexpression inhibited proliferative, migratory and invasive abilities of ovarian cancer cells while enhancing cell apoptosis and improving cell sensitivity to cisplatin in ovarian cancer. Further, miR-30a-5p targeted to chromodomain helicase DNA binding protein 1 (CHD1) and inhibited the expression of CHD1 in ovarian cancer. Moreover, rescue experiments manifested that miR-30a-5p weakened cisplatin resistance and the cellular process of ovarian cancer by mediating CHD1. Besides, miR-30a-5p regulated CHD1 expression to suppress Wnt/β-catenin signaling in ovarian cancer. The findings were verified by in vivo experiments. This article elucidated that miR-30a-5p/CHD1 axis inhibited the cellular process and enhanced cisplatin sensitivity of ovarian cancer cells through the Wnt/β-catenin pathway, which may provide a useful direction for the targeted chemotherapy of ovarian cancer.

Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4

Drug resistance is a key factor in the treatment failure of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) plays a crucial role in tumor chemotherapy resistance. However, the potential mechanism of Nrf2 regulating DNA mismatch repair (MMR) pathway to mediate gene-instability drug resistance in AML is still unclear. Here, it was found that Nrf2 expression was closely related to the disease progression of AML as well as highly expressed in AML patients with poor prognostic gene mutations. Meanwhile, it was also found that the expression of Nrf2 was significantly negatively correlated with DNA MMR gene replication factor C4 (RFC4) in AML. CHIP analysis combined with luciferase reporter gene results further showed that Nrf2 may inhibit the expression of RFC4 by its interaction with the RFC4 promoter. In vitro and vivo experiments showed that the overexpression of Nrf2 decreased the killing effect of chemotherapy drug cytarabine (Ara-C) on leukemia cells and inhibited the expression of RFC4. Mechanistically, The result that Nrf2-RFC4 axis mediated AML genetic instability drug resistance might be received by activating the JNK/NF-κB signaling pathway. Taken together, these findings may provide a new idea for improving AML drug resistance.

FAT10 promotes chemotherapeutic resistance in pancreatic cancer by inducing epithelial-mesenchymal transition via stabilization of FOXM1 expression

Pancreatic cancer (PC) is one of the deadliest malignant tumors, and its resistance to gemcitabine chemotherapy is the primary reason for poor prognosis in patients. Ubiquitin-like protein FAT10 has recently been reported to promote tumor chemotherapy resistance. In this study, the expression of FAT10 in PC was significantly higher than that in adjacent noncancerous tissues. Increased expression of FAT10 in PC was related to a late TNM stage and decreased overall survival. Functional experiments revealed that downregulating the expression of FAT10 inhibits the proliferation and epithelial-mesenchymal transition (EMT) of PC cells, promotes the apoptosis of PC cells, and enhances sensitivity to gemcitabine chemotherapy. In addition, upregulation of FAT10 increased the expression of FOXM1 protein. The effect of downregulating FAT10 was reversed by FOXM1 overexpression, and FOXM1 knockdown inhibited EMT driven by FAT10 overexpression. Mechanistically, FAT10 stabilized the expression of FOXM1 by competing with ubiquitin to bind FOXM1 and inhibiting the ubiquitination-mediated degradation of FOXM1. In conclusion, the FAT10-FOXM1 axis is a pivotal driver of PC proliferation and gemcitabine resistance, and the results provide novel insights into chemotherapy resistance in PC.

Circular RNAs and Drug Resistance in Genitourinary Cancers: A Literature Review

Simple SummaryDrug resistance to systematic treatment in genitourinary tumors severely aggravated the burden on patients and society. Multiple mechanisms were involved in drug resistance. As typical non-coding RNAs, circRNAs play a critical role in the onset and development of cancers and several studies implied their function in the regulation of drug resistance. Here, we reviewed the investigations of circRNAs’ behavior in drug resistance of genitourinary cancers and summarized the underlying mechanisms. This review emphasized the essential role of circRNAs in drug resistance development and also pointed out the potential topics that need further investigations in the future.In recent years, systematic treatment has made great progress in genitourinary tumors. However, some patients develop resistance to the treatments, resulting in an increase in mortality. Circular RNAs (circRNAs) form a class of non-coding RNAs with high stability and significant clinical relevance. Accumulating evidence indicates that circRNAs play a vital role in cancer development and tumor chemotherapy resistance. This review summarizes the molecular and cellular mechanisms of drug resistance mediated by circRNAs to common drugs used in the treatment of genitourinary tumors. Several circRNAs were identified to regulate the responsiveness to systemic treatments in genitourinary tumors, including chemotherapies such as cisplatin and targeted therapies such as enzalutamide. Canonically, cicrRNAs participate in the competing endogenous RNA (ceRNA) network, or in some cases directly interact with proteins, regulate downstream pathways, and even some circRNAs have the potential to produce proteins or polypeptides. Several cellular mechanisms were involved in circRNA-dependent drug resistance, including autophagy, cancer stem cells, epithelial-mesenchymal transition, and exosomes. The potential clinical prospect of circRNAs in regulating tumor drug resistance was also discussed.

Up-regulation of microRNA miR-101-3p enhances sensitivity to cisplatin via regulation of small interfering RNA (siRNA) Anti-human AGT4D and autophagy in non-small-cell lung carcinoma (NSCLC)

ABSTRACT The emergence of drug resistance hinders the treatment of malignant tumors, and autophagy plays an important role in tumor chemotherapy resistance. However, its mechanism in non-small cell lung cancer (NSCLC) has not been well-researched. We aim to investigate the role of miR-101-3p in cisplatin-resistant via regulation of autophagy-related protein 4D (ATG4D) and autophagy. Cell viability, apoptosis, fluorescence intensity of GFP-LC3 and RFP-GFP-LC3 were determined using Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and Laser scanning confocal microscope analysis, respectively. The levels of LC3II/LC3I, P62 and ATG4D were detected by Western blot. The results showed that the sensitivity to cisplatin in NSCLC cells was up-regulated by miR-101-3p mimics treatment, inducing promoting cell apoptosis and inhibiting autophagy. Further mechanistic study identified that ATG4D was a direct target of miR-101-3p. Moreover, ATG4D siRNA also could reverse miR-101-3p inhibitor-induced the up-regulation of ATG4D and the ration of LC3II/LC3I, the down-regulation of p62 expression. Our findings indicated that miR-101-3p could regulate sensitivity to cisplatin of NSNCC cells by regulating autophagy mediated by ATG4D. Therefore, miR-101-3p may act as a potential therapeutic target for the treatment of NSCLC.

TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of β-catenin.

TRAF4 plays an important role in the development and progression of breast cancer, but its impact on chemotherapy resistance is as yet, however, poorly understood. Western blotting, immunoprecipitation, and immunofluorescence staining were used to identify and verify that TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated β-catenin degradation. Cell proliferation analysis and Flow cytometry analysis were utilized to detect TRAF4's function on the growth-inhibitory effect of etoposide. Immunohistochemistry was used to detect the expression of TRAF4, SIAH1, and β-catenin. Statistical analysis was used to analyze the relationships between them with clinical parameters and curative effect of chemotherapy pathologically. Our results suggested that TRAF4 prevents SIAH1-mediated β-catenin degradation. TRAF4 was a novel substrate of SIAH1 and the TRAF domain of TRAF4 was critical for binding to SIAH1. TRAF4 reduced the growth-inhibitory effect of etoposide via reducing the number of S-phase cells and suppressing cell apoptosis. Concordantly, we found that breast cancer patients with a low-TRAF4 expression benefited most from chemotherapy, who had higher tumor volume reduction rate and better pathological response, while, the high-TRAF4 expression group had lower tumor volume reduction rate and poor pathological response. TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated β-catenin degradation, which explains the protective effect of TRAF4 on β-catenin during cell stress and links TRAF4 to chemotherapy resistance in tumors. These findings implicated a novel pathway for the oncogenic function of TRAF4.

ROS enhances the cytotoxicity of cisplatin by inducing apoptosis and autophagy in tongue squamous cell carcinoma cells.

Cisplatin is one of the most widely used anticancer agents for patients with tongue squamous cell carcinoma (TSCC), but its efficacy is limited by chemoresistance. Accumulated evidence has demonstrated that reactive oxygen species (ROS) plays a critical role in multiple tumor chemotherapy resistance. In the present study, we aimed to investigate the role of ROS in cisplatin resistance of TSCC and explore its underlying molecular mechanism in vitro. Our results showed that pre-treatment with ROS scavenger N-acetylcysteine reduced cisplatin-induced cytotoxicity, autophagy, and apoptosis in TSCC cells. Down-regulation of intracellular ROS attenuated apoptosis and autophagy of TSCC cisplatin-resistant CAL27/CDDP cells by reversing the inhibition of p38MAPK/mTOR pathway. Taken together, these findings suggest that down-regulation of intracellular ROS reduces the cytotoxicity of cisplatin by inhibiting apoptosis and autophagy in TSCC cells involving p38MAPK/mTOR mediated pathway. Low intracellular ROS levels may be one of the main mechanisms of cisplatin resistance in TSCC.

MiRNAs: A Promising Target in the Chemoresistance of Bladder Cancer.

Chemotherapy is an important cancer treatment method. Tumor chemotherapy resistance is one of the main factors leading to tumor progression. Like other malignancies, bladder cancer, especially muscle-invasive bladder cancer, is prone to chemotherapy resistance. Additionally, only approximately 50% of muscle-invasive bladder cancer responds to cisplatin-based chemotherapy. miRNAs are a class of small, endogenous, noncoding RNAs that regulate gene expression at the posttranscriptional level, which results in the inhibition of translation or the degradation of mRNA. In the study of miRNAs and cancer, including gastric cancer, prostate cancer, liver cancer, and colorectal cancer, it has been found that miRNAs can regulate the expression of genes related to tumor resistance, thereby promoting the progression of tumors. In bladder cancer, miRNAs are also closely related to chemotherapy resistance, suggesting that miRNAs can be a new therapeutic target for the chemotherapy resistance of bladder cancer. Therefore, understanding the mechanisms of miRNAs in the chemotherapy resistance of bladder cancer is an important foundation for restoring the chemotherapy sensitivity of bladder cancer and improving the efficacy of chemotherapy and patient survival. In this article, we review the role of miRNAs in the development of chemotherapy-resistant bladder cancer and the various resistance mechanisms that involve apoptosis, the cell cycle, epithelial-mesenchymal transition (EMT), and cancer stem cells (CSCs).

Abstract 4554: IL-17-CXCR2 axis promotes breast cancer metastasis and therapy resistance through facilitating recruitment of neutrophils

Abstract Breast cancer is one of the most common cancer types that happens to global females. The major challenges for breast cancer include therapy resistance and metastasis. Various factors and cancer-related immune cells are involved in tumor chemotherapy resistance process, including pro-inflammatory cytokine, interleukin (IL) 17, CXCR2 ligands (pro-inflammatory chemokines) and neutrophils. They are the key players for promoting cancer progression, and numerous reports indicated them as a potential therapeutic target for various cancer types including breast cancer. However, the detailed mechanism(s) remains unclear. In the present study, we investigate the role of neutrophils in chemotherapy resistance and metastasis in breast cancer. In our previous study, we have observed increased levels of CXCR2 ligands in chemotherapy-resistant cells comparing with Cl66 parent cells. In this study, we observed upregulated IL17, IL17 receptor (IL-17R), granulocyte colony stimulating factor (GCSF) by qRT- PCR in resistant cells compared with parent cells. We further evaluated the protein levels of CXCR2 and its ligands, IL17 and its receptor, frequencies of neutrophils and T-helper 17 (Th17) cells in primary and metastatic tumors through using immunohistochemistry method. There were higher levels of IL17R, CXCR2, and CXCR2 ligands in metastatic tumor sites in comparison to the primary tumor sites. Moreover, we observed increased levels of IL17R, CXCR2, CXCR2 ligands together with the higher frequencies of neutrophils and Th17 cells in resistant tumors than Cl66 tumors. At the same time, tumor cells treated with IL-17 increased its proliferation rate and its expression of CXCL1 & CXCL5; and the increase was all in a concentration-dependent manner. In addition, the increase of CXCR2 ligands by IL17 was inhibited when we treated the tumor cells with ERK and NF-KB signaling inhibitors, indicating both pathways are involved in the regulation of IL17-induced CXCR2 ligands secretion. Together, our data demonstrate an IL17-CXCR2 ligands axis plays protumorigenic inflammation, facilitating therapy resistance and metastasis through recruited neutrophils. Citation Format: Lingyun Wu, Sugandha Saxena, Mohammad Awaji, Bhawna Sharma, Rakesh Singh. IL-17-CXCR2 axis promotes breast cancer metastasis and therapy resistance through facilitating recruitment of neutrophils [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4554.

MicroRNA-137 inhibits autophagy and chemosensitizes pancreatic cancer cells by targeting ATG5.

Autophagy play an important role in tumor chemotherapy resistance. It has been reported that miR-137 expression was reducedand involved in the regulation of sensitivity of PC cells to chemotherapy. However, little is known about the underlying molecular mechanisms. In this study, we hypothesized that miR-137 might sensitize PC cells to chemotherapy thought regulating cell autophagy. Cell survival was determined with MTT assay. Apoptotic cells were assessed with flow cytometric analysis. Fluorescence intensity of GFP-LC3 and RFP-GFP-LC3 were examined with immunofluorescence analysis to determine the autophagy and autophagic flux level. Western blotting assay was used to determine protein expression levels of LC3II/LC3I, P62, FUNDC1 and ATG5. mRNA expression level of miR-137 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Dual-luciferase reporter assay was used to evaluate the directly binding of miR-137 with its targets. Xenograft model was setup to evaluate tumor growth. The results showed that doxorubicin (Dox) induced autophagy but downregulated the expression level of miR-137 in pancreatic cancer (PC) cells. In turn, overexpression of miR-137 enhanced the effect of Dox on decreasing cell survival, inducing cell apoptosis and inhibiting autophagy rather than influencing autophagic flux in PC cells. Further mechanistic study identified that ATG5 was a direct target of miR-137. Moreover, overexpression of ATG5 dramatically reversed the promotion of apoptosis and inhibition of autophagy mediated by higher expression level of miR-137. We also demonstrated that miR-137 sensitized PANC-1 cells to Dox through inhibiting ATG5 and autophagy in vivo. Our findings demonstrated for the first time that miR-137 was able to promote sensitivity of PC cells to chemotherapy via inhibition of autophagy mediated by ATG5. Therefore, miR-137 may act as a potential therapeutic target for pancreatic cancer.

Long non-coding RNA FTH1P3 activates paclitaxel resistance in breast cancer through miR-206/ABCB1.

Emerging evidence has indicated the important function of long non‐coding RNAs (lncRNAs) in tumour chemotherapy resistance. However, the underlying mechanism is still ambiguous. In this study, we investigate the physiopathologic role of lncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) on the paclitaxel (PTX) resistance in breast cancer. Results showed that lncRNA FTH1P3 was up‐regulated in paclitaxel‐resistant breast cancer tissue and cells (MCF‐7/PTX and MDA‐MB‐231/PTX cells) compared with paclitaxel‐sensitive tissue and parental cell lines (MCF‐7, MDA‐MB‐231). Gain‐ and loss‐of‐function experiments revealed that FTH1P3 silencing decreased the 50% inhibitory concentration (IC50) value of paclitaxel and induced cell cycle arrest at G2/M phase, while FTH1P3‐enhanced expression exerted the opposite effects. In vivo, xenograft mice assay showed that FTH1P3 silencing suppressed the tumour growth of paclitaxel‐resistant breast cancer cells and ABCB1 protein expression. Bioinformatics tools and luciferase reporter assay validated that FTH1P3 promoted ABCB1 protein expression through targeting miR‐206, acting as a miRNA “sponge.” In summary, our results reveal the potential regulatory mechanism of FTH1P3 on breast cancer paclitaxel resistance through miR‐206/ABCB1, providing a novel insight for the breast cancer chemoresistance.

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

Drug resistance is a primary cause of chemotherapeutic failure; however, how this resistance develops is complex. A comprehensive understanding of chemotherapeutic resistance mechanisms may aid in identifying more effective drugs and improve the survival rates of patients with cancer. Insulin-like growth factor 1 receptor (IGF1R), a member of the insulin receptor family, has been extensively assessed for biological activity, and its putative contribution to tumor cell development and progression. Furthermore, researchers have attended to drugs that target IGF1R since IGF1R functions as a membrane receptor. However, how IGF1R participates in chemotherapeutic resistance remains unclear. Therefore, the present study described the IGF1R gene and its associated signaling pathways, and offered details of IGF1R-induced tumor chemoresistance associated with promoting cell proliferation, inhibition of apoptosis, regulation of ATP-binding cassette transporter proteins and interactions with the extracellular matrix. The present study offered additional explanations for tumor chemotherapy resistance and provided a theoretical basis of IGF1R and its downstream pathways for future possible chemotherapy treatment options.

Adipose‑derived mesenchymal stem cells attenuate cisplatin‑induced apoptosis in epithelial ovarian cancer cells.

Environment-mediated drug resistance (EMDR) serves an important role in tumor chemotherapy resistance. Adipose‑derived mesenchymal stem cells (ADSC) are an important component of the tumor microenvironment. However, the role of ADSC in EMDR remains unclear. Therefore, in order to clarify whether ADSCs contribute to the cisplatin‑mediated apoptosis in epithelial ovarian cancer (EOC), the present study isolated ADSCs from the omentum of women with benign disease and collected the ADSC culture medium as conditioned medium. Subsequently, it was revealed that ADSCs decreased the sensitivity of EOC cells to cisplatin via an MTT assay. In addition, it was revealed that ADSCs may reduce cisplatin-induced apoptosis in EOC cells, as determined by Hoechst staining and flow cytometric analysis. Additionally, a lower level of cleaved caspase‑3 was observed, accompanied with decreased intracellular platinum accumulation in EOC cells indirectly co‑cultured with ADSCs. In conclusion, the findings of the present study suggested that ADSCs reduced cisplatin‑induced apoptosis and the intracellular level of platinum in EOC cells, which in turn resulted in cisplatin resistance. Therefore, ADSCs may serve as a therapeutic target for recurrent EOC.

The combination of Bleomycin with TRAIL agonists or PKC inhibitors sensitizes solid tumor cells to BLM-mediated apoptosis: new strategies to overcome chemotherapy resistance of tumors

In this study we evaluated the effects of low dose of bleomycin in an associative treatment strategy in solid tumor cells. For this purpose, Human and murine colon cancer (SW480, HCT8, and CT26), and murine melanoma (B16-F10) cells were treated with different agents including protein kinase C, and c-jun NH2-terminal kinase inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand. Apoptosis was identified by morphological criteria. Reactive oxygen species are evaluated by flow cytometry. Our data showed that bleomycin (100 µM) induced apoptosis in all the four cell lines tested with a level ranging from 30 to 60%. However, at lower dose (25 µM), bleomycin was less efficient to trigger apoptosis. In contrast, when bleomycin (25 µM) was combined with the protein kinase C inhibitor chelerythrine, or tumor necrosis factor-related apoptosis-inducing ligand, it elicited more apoptotic cell death ranging from 40 to 75%, depending on the cell type, whereas when it was associated with the c-jun NH2-terminal kinase inhibitor SP600125, bleomycin displayed different cell death responses. If bleomycin and SP600125 enhanced apoptosis in two colon cancer cells, HCT-8, and CT26, they reduced to 50% apoptosis in the melanoma B16-F10 cells, and were not synergistic in the human colon cancer cells, SW480. This synergism seemed to rely partially to reactive oxygen species, because N-acetyl cysteine inhibited apoptosis in some cells and with some agents. These findings indicate that tumor necrosis factor-related apoptosis-inducing ligand, and protein kinase C inhibition can represent candidates for improved cancer chemotherapy.