Resistant Human Cancer Research Articles

More subtle microsatellite instability better predicts fluorouracil insensitivity in colorectal cancer patients

Microsatellite instability (MSI) is now widely used as an indispensable biomarker. However, the relationship between MSI-H (high) and defective DNA mismatch repair (MMR) is not as straightforward as has been expected. Genome-edited cells carrying Lynch syndrome mutations do not exhibit drastic MSI typical in MSI-H (i.e. Type B) but more subtle MSI (i.e. Type A). In this study, we explored a connection between Type A MSI and 5-fluorouracil (5-FU) resistance in colorectal cancer patients. Using our precision and high-resolution MSI assay technique, tumour microsatellites were analysed in 30 colorectal cancer patients treated with FOLFOX or CAPOX. Among 30 tumours, eleven (37%) were judged as Type A MSI-positive. In Type A MSI+ tumours, the patient response to fluoropyrimidine and oxaliplatin was significantly poor (Fisher’s exact test, p = 0.021). Accordingly, median PFS and OS were significantly poor in Type A+ patients (log-rank test, p < 0.001/p = 0.009). Type A MSI was an independent predictor of patient prognosis in this pilot cohort (Cox regression analysis, p = 0.003). Thus, more subtle Type A MSI better predicts fluoropyrimidine insensitivity in colorectal cancer patients, which may shed light on a hitherto overlooked connection between the MSI phenotypes and drug resistance in human cancer.

Pan-cancer analysis of disulfidptosis with potential implications in prognosis, immune microenvironment, and drug resistance in human cancer.

To get a systematic assessment of disulfidptosis-related genes across human cancers and explore the predictive role of disulfidptosis in cancer drug sensitivity. We developed a score-level model to quantify the level of disulfidptosis in 33 human cancers using TCGA data. The mRNA expression and protein levels of disulfidptosis-related genes in human cancer cells and tissues were detected and retrieved from the Human Protein Atlas. Multiomics bioinformatic analyses were performed to evaluate disulfidptosis-related gene characteristics as well as the effect of disulfidptosis on the cancer immune microenvironment and drug resistance. Thirty cancers showed significantly different expression levels of disulfidptosis-related genes between normal and tumor samples. The mRNA expression and protein level of disulfidptosis-related genes were consistent with TCGA databases in lung cancer and hepatocellular carcinoma. We also found that altered levels of the disulfidptosis score expression were usually related to patient prognosis, and high expression of disulfidptosis-related genes was associated with drug resistance in different cancer types. Our study illustrates the characterization of disulfidptosis in multiple cancer types and highlights its potential value as a predictive biomarker of drug response, which can pave the way for further investigation of the prognostic and therapeutic potential of disulfidptosis.

Kinesin Facilitates Phenotypic Targeting of Therapeutic Resistance in Advanced Prostate Cancer.

Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes in patients with metastatic castration-resistant prostate cancer. Previous work showed that dynamic interconversions between epithelial-mesenchymal transition to mesenchymal-epithelial transition defines the phenotypic landscape of prostate tumors, as a potential driver of the emergence of therapeutic resistance. In this study, we use in vitro and in vivo preclinical MDA PCa patient-derived xenograft models of resistant human prostate cancer to determine molecular mechanisms of cross-resistance between antiandrogen therapy and taxane chemotherapy, underlying the therapeutically resistant phenotype. Transcriptomic profiling revealed that resistant and sensitive prostate cancer C4-2B cells have a unique differential gene signature response to cabazitaxel. Gene pathway analysis showed that sensitive cells exhibit an increase in DNA damage, while resistant cells express genes associated with protein regulation in response to cabazitaxel. The patient-derived xenograft model specimens are from patients who have metastatic lethal castration-resistant prostate cancer, treated with androgen deprivation therapy, antiandrogens, and chemotherapy including second-line taxane chemotherapy, cabazitaxel. Immunohistochemistry revealed high expression of E-cadherin and low expression of vimentin resulting in redifferentiation toward an epithelial phenotype. Furthermore, the mitotic kinesin-related protein involved in microtubule binding and the SLCO1B3 transporter (implicated in cabazitaxel intracellular transport) are associated with resistance in these prostate tumors. Combinational targeting of kinesins (ispinesib) with cabazitaxel was more effective than single monotherapies in inducing cell death in resistant prostate tumors. Implications: Our findings are of translational significance in identifying kinesin as a novel target of cross-resistance toward enhancing therapeutic vulnerability and improved clinical outcomes in patients with advanced prostate cancer.

Potential applications of antofine and its synthetic derivatives in cancer therapy: structural and molecular insights.

Cancer is a major global health challenge, being the second leading cause of morbidity and mortality after cardiovascular disease. The growing economic burden and profound psychosocial impact on patients and their families make it urgent to find innovative and effective anticancer solutions. For this reason, interest in using natural compounds to develop new cancer treatments has grown. In this respect, antofine, an alkaloid class found in Apocynaceae, Lauraceae, and Moraceae family plants, exhibits promising biological properties, including anti-inflammatory, anticancer, antiviral, and antifungal activities. Several molecular mechanisms have been identified underlying antofine anti-cancerous effects, including the inhibition of nuclear factor κB (NF-κB) and AKT/mTOR signaling pathways, epigenetic inhibition of protein synthesis, ribosomal targeting, induction of apoptosis, inhibition of DNA synthesis, and cell cycle arrest. This study discusses the molecular structure, sources, photochemistry, and anticancer properties of antofine in relation to its structure-activity relationship and molecular targets. Then, examine in vitro and in vivo studies and analyze the mechanisms of action underpinning antofine efficacy against cancer cells. This review also discusses multidrug resistance in human cancer and the potential of antofine in this context. Safety and toxicity concerns are also addressed as well as current challenges in antofine research, including the need for clinical trials and bioavailability optimization. This review aims to provide comprehensive information for more effective natural compound-based cancer treatments.

ECRG2/SPINK7 Tumor Suppressor as Modulator of DNA Damage Response.

Esophageal Cancer-Related Gene 2 (ECRG2), also known as Serine Peptidase Inhibitor Kazal type 7 (SPINK7), is a novel tumor suppressor gene from the SPINK family of genes that exhibits anticancer potential. ECRG2 was originally identified during efforts to discover genes involved in esophageal tumorigenesis. ECRG2 was one of those genes whose expression was absent or reduced in primary human esophageal cancers. Additionally, absent or reduced ECRG2 expression was also noted in several other types of human malignancies. ECRG2 missense mutations were identified in various primary human cancers. It was reported that a cancer-derived ECRG2 mutant (valine to glutamic acid at position 30) failed to induce cell death and caspase activation triggered by DNA-damaging anticancer drugs. Furthermore, ECRG2 suppressed cancer cell proliferation in cultured cells and grafted tumors in animals and inhibited cancer cell migration/invasion and metastasis. ECRG2 also was identified as a negative regulator of Hu-antigen R (HuR), an oncogenic RNA-binding protein that is known to regulate mRNA stability and the expression of transcripts corresponding to many cancer-related genes. ECRG2 function is important also for the regulation of inflammatory responses and the maintenance of epithelial barrier integrity in the esophagus. More recently, ECRG2 was discovered as one of the newest members of the pro-apoptotic transcriptional targets of p53. Two p53-binding sites (BS-1 and BS-2) were found within the proximal region of the ECRG2 gene promoter; the treatment of DNA-damaging agents in cancer cells significantly increased p53 binding to the ECRG2 promoter and triggered a strong ECRG2 promoter induction following DNA damage. Further, the genetic depletion of ECRG2 expression significantly impeded apoptotic cell death induced by DNA damage and wild-type p53 in cancer cells. These findings suggest that the loss of ECRG2 expression, commonly observed in human cancers, could play important roles in conferring anticancer drug resistance in human cancers. Thus, ECRG2 is a novel regulator in DNA damage-induced cell death that may also be a potential target for anticancer therapeutics.

Complex formation of ML324, the histone demethylase inhibitor, with essential metal ions: Relationship between solution chemistry and anticancer activity

N-(3-(dimethylamino)propyl-4-(8-hydroxyquinolin-6-yl)benzamide (ML324, HL) is a potent inhibitor of the iron-containing histone demethylase KDM4, a recognized potential target of cancer therapeutics. Herein, we report the proton dissociation and complex formation processes of ML324 with essential metal ions such as Fe(II), Fe(III), Cu(II) and Zn(II) using UV–visible, fluorescence, electron paramagnetic resonance and 1H NMR spectroscopic methods. The electrochemical behaviour of the copper and iron complexes was characterized by cyclic voltammetry and spectroelectrochemistry. The solid phase structure of ML324 analysed by X-ray crystallography is also provided. Based on the solution equilibrium data, ML324 is present in solution in H2L+ form with a protonated dimethylammonium moiety at pH 7.4, and this (N,O) donor bearing ligand forms mono and bis complexes with all the studied metal ions and the tris-ligand species is also observed with Fe(III). At pH 7.4 the metal binding ability of ML324 follows the order: Fe(II) < Zn(II) < Cu(II) < Fe(III). Complexation with iron resulted in a negative redox potential (E'1/2 = −145 mV vs. NHE), further suggesting that the ligand has a preference for Fe(III) over Fe(II). ML324 was tested for its anticancer activity in chemosensitive and resistant human cancer cells overexpressing the efflux pump P-glycoprotein. ML324 exerted similar activity in all tested cells (IC50 = 1.9–3.6 μM). Co-incubation and complexation of the compound with Cu(II) and Zn(II) had no impact on the cytotoxicity of ML324, whereas Fe(III) decreased the toxicity in a concentration-dependent manner, and this effect was more pronounced in the multidrug resistant cells.

Abstract 1669: KRAS G12X mutants display differential preferences in downstream effector binding

Abstract KRAS is among the most frequently mutated oncogenic driver proteins in human cancers including lung, colorectal, and pancreatic cancers. Activating KRAS mutants cause increased cell proliferation through direct binding and overactivation of effector proteins. Effector activation preference is driver mutation specific, as KRAS G12D and G12C purportedly bind both RAF and PI3K, whereas G12R has been reported to bind RAF but not PI3K. The mechanisms of effector binding of G12S action are under-investigated. Furthermore, most KRAS mutations remain clinically untreatable, as clinically approved KRAS inhibitors (KRASi) are currently limited to specifically targeting G12C. While experimental non-G12C inhibitors are being developed, resistance mechanisms to non-G12C mutations—including G12D/R/S/V—remain relatively understudied. We set out to characterize the binding efficiency of KRAS to RAF1 and the PI3K subunit p110α, and to understand how isoforms differ in inhibitor resistance strategies. Our findings suggest that significant variances in KRAS mutation-specific effector binding preference exist and are cell line dependent. We performed proximity ligation based immunofluorescence assays (PLA) on an isogenic panel of human colorectal SW48 KRAS cells with G12C/D/R/S/V or wildtype. SW48 cells with G12S significantly prefer the KRAS-RAF1 mode of binding over otherwise isogenic WT cells, and G12V homologs prefer PI3K. Our findings suggest that in this model, G12R cells have no specific preference of one binding mode over the other. We hypothesize that G12 chemistry drives effector binding preference and that G12X inhibitor resistant cell cultures will demonstrate variant mechanisms of resistance in line with their preferred binding partner. Ongoing studies will further characterize understudied RAS isoform biology and evaluate the links between isoform chemistry and mechanisms of inhibitor resistance. These studies will expand our mechanistic knowledge of the interplay between G12X chemistry and adaptive resistance in human cancer. Citation Format: Leonard J. Ash, Ottavia Bourdain, Dennis Lam, Shlomo S. Pallas, Andrew L. Wolfe. KRAS G12X mutants display differential preferences in downstream effector binding [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 1669.

PROM2 overexpression induces metastatic potential through epithelial-to-mesenchymal transition and ferroptosis resistance in human cancers.

Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin-2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio-target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma. Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial-to-mesenchymal transition (EMT) marker expression and ferroptosis resistance. This was also found in renal cell carcinoma and triple negative breast cancer patient-derived xenograft models. Using an oligonucleotide anti-sense anti-PROM2, we efficaciously decreased PROM2 expression and prevented metastases in melanoma xenografts. We also demonstrated that PROM2 was implicated in an aggravation loop, contributing to increase the metastatic burden both in murine metastatic models and in patients with metastatic melanoma. The metastatic burden is closely linked to PROM2 expression through the expression of EMT markers and ferroptosis cell death resistance in a deterioration loop. Our results open the way for further studies using PROM2 as a bio-target in resort situations in human metastatic melanoma and also in other cancer types.

Medicinal Chemistry and NMR Driven Discovery of Novel UDP-glucuronosyltransferase 1A Inhibitors That Overcome Therapeutic Resistance in Cells

The UDP glucuronosyltransferases (UGT) deactivate many therapeutics via glucuronidation while being required for clearance of normal metabolites and xenobiotics. There are 19 UGT enzymes categorized into UGT1A and UGT2B families based on sequence conservation. This presents a challenge in terms of targeting specific UGTs to overcome drug resistance without eliciting overt toxicity. Here, we identified for the first time that UGT1A4 is highly elevated in acute myeloid leukemia (AML) patients and its reduction corresponded to objective clinical responses. To develop inhibitors to UGT1A4, we leveraged previous NMR-based fragment screening data against the C-terminal domain of UGT1A (UGT1A-C). NMR and medicinal chemistry strategies identified novel chemical matter based on fragment compounds with the capacity to bind ∼20 fold more tightly to UGT1A-C (Kd ∼ 600 μM vs ∼30 μM). Some compounds differentially inhibited UGT1A4 versus UGT1A1 enzyme activity and restored drug sensitivity in resistant human cancer cells. NMR-based NOE experiments revealed these novel compounds recognised a region distal to the catalytic site suggestive of allosteric regulation. This binding region is poorly conserved between UGT1A and UGT2B C-terminal sequences, which otherwise exhibit high similarity. Consistently, these compounds did not bind to the C-terminal domain of UGT2B7 nor a triple mutant of UGT1A-C replaced with UGT2B7 residues in this region. Overall, we discovered a site on UGTs that can be leveraged to differentially target UGT1As and UGT2Bs, identified UGT1A4 as a therapeutic target, and found new chemical matter that binds the UGT1A C-terminus, inhibits glucuronidation and restores drug sensitivity.

Understanding and Targeting the Epigenetic Regulation to Overcome EGFR-TKIs Resistance in Human Cancer.

The occurrence and progression of cancer are the results of the dysregulation of genetics and epigenetics. Epigenetic regulation can reversibly affect gene transcription activity without changing DNA structure. Covalent modification of histones is crucial in the epigenetic regulation of gene expression. Furthermore, epidermal growth factor receptor (EGFR) significantly affects cell tumorigenesis, proliferation, antitumor drug resistance, etc. Overexpression of EGFR promotes cancer development. Therefore, EGFR-targeted drugs have become the focus of tumor therapy. With the advent of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), EGFR-TKIs resistance, which occurs about half a year to a year, has become an obstacle in cancer treatment. The objective of this study is to discuss the ways to overcome EGFR-TKIs resistance in a variety of tumors. The combination therapy of epigenetic drugs and other drugs is used. The combination of the two drugs can overcome the resistance of EGFR-TKIs and prolong the survival of patients. This article depicts the concepts of epigenetics and the mechanism of EGFR-TKIs resistance and then illustrates the relationship between epigenetic mechanisms and EGFR-TKIs resistance. Finally, it discusses the clinical research and the latest patents for using epigenetic drugs to reverse EGFR-TKIs resistance in human cancer. In the future, more novel targets may be discovered for overcoming resistance to EGFR-TKIs, not just on histone deacetylases (HDACs). The dosing course and mode of administration of the combination therapy containing epigenetic drugs need further study. This review provides new ideas for using epigenetic agents to overcome EGFR-TKIs resistance.

Susceptibility of various human cancer cell lines to nanosecond and microsecond range electrochemotherapy: Feasibility of multi-drug cocktails

Electrochemotherapy (ECT) involves combining anticancer drugs with electroporation, which is induced by pulsed electric fields (PEFs), while the effects vary in effectiveness based on the specific parameters of the electrical pulses and susceptibility of the cells to a specific drug. In this work, we utilized conventional microsecond electroporation protocols (0.8 – 1.5 kV/cm × 100 μs × 8, 1 Hz) and the new modality of nanosecond pulses (4 and 8 kV/cm × 500 ns × 100, 1 kHz and 1 MHz), which are compressed into a high frequency burst. Sensitive and resistant lung, breast and ovarian human cancer cell lines were used in the study. In order to overcome drug-resistance, we have investigated the feasibility to use anticancer drug cocktails i.e., bleomycin and cisplatin combinations with metformin, vinorelbine and Dp44mT. The different susceptibility of various human cancer cells lines to electric pulses was determined, the efficacy of ECT was characterized and the type of cell death depending on the combinations of drugs was investigated. The results indicate that synergistic effects of PEFs with drug cocktails may be used to overcome drug-resistance in cancer, while the application of nsPEF provides more flexibility in parametric protocols and modulation of cancer cell death.

TRIM21-Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers.

Ferroptosis, an iron-dependent form of regulated cell death driven by excessive accumulation of lipid peroxides, has become a promising strategy in cancer treatment. Cancer cells exploit antioxidant proteins, including Ferroptosis Suppressor Protein 1 (FSP1), to prevent ferroptosis. In this study, it is found that the E3 ubiquitin ligase TRIM21 bound to FSP1 and mediated its ubiquitination on K322 and K366 residues via K63 linkage, which is essential for its membrane translocation and ferroptosis suppression ability. It is further verified the protective role of the TRIM21-FSP1 axis in RSL3-induced ferroptosis in cancer cells and a subcutaneous tumor model. Moreover, TRIM21 is highly expressed in multiple gastrointestinal (GI) tumors, and its expression is further stimulated upon ferroptosis induction in cancer cells and the KPC mouse model. In summary, This study identifies TRIM21 as a negative regulator of ferroptosis through K63 ubiquitination of FSP1, which can serve as a therapeutic target to enhance the chemosensitivity of tumors based on ferroptosis induction.

YAP at the Crossroads of Biomechanics and Drug Resistance in Human Cancer.

Biomechanical forces are of fundamental importance in biology, diseases, and medicine. Mechanobiology is an emerging interdisciplinary field that studies how biological mechanisms are regulated by biomechanical forces and how physical principles can be leveraged to innovate new therapeutic strategies. This article reviews state-of-the-art mechanobiology knowledge about the yes-associated protein (YAP), a key mechanosensitive protein, and its roles in the development of drug resistance in human cancer. Specifically, the article discusses three topics: how YAP is mechanically regulated in living cells; the molecular mechanobiology mechanisms by which YAP, along with other functional pathways, influences drug resistance of cancer cells (particularly lung cancer cells); and finally, how the mechanical regulation of YAP can influence drug resistance and vice versa. By integrating these topics, we present a unified framework that has the potential to bring theoretical insights into the design of novel mechanomedicines and advance next-generation cancer therapies to suppress tumor progression and metastasis.

Collaborative modification strategy to develop a highly selective fluorescent probe for human UDP-glucuronosyltransferase 1A10

UDP-glucuronosyltransferase 1A10 (UGT1A10) is an important phase II human metabolic enzyme. However, few methods are available to facilely monitor the function of UGT1A10 in biological systems. Here we report the first sensitive and selective fluorescent “off–on” UGT1A10 probe substrate UPr6. Using a collaborative modification strategy, we introduced a rigid propyl morpholine group to the amide and a methoxy group next to 4′-phenoxy of the 4-phenyl-1,8-naphthalimide skeleton to obtain UPr6. Visualization methods were established to evaluate the function of UGT1A10 in living cells, rat tissues, and zebrafish. From a Chinese herbal medicine compound library, two natural products EUC and DAP from licorice were discovered as potent UGT1A10 inhibitors, which remarkably improved the sensitivity of CPT-11 against a resistant human cancer cell line. This work established a feasible strategy to rationally design isoform-specific UGT probe substrates.

New Phenylspirodrimanes from the Sponge-Associated Fungus Stachybotrys chartarum MUT 3308

Two phenylspirodrimanes, never isolated before, stachybotrin J (1) and new stachybocin G (epi-stachybocin A) (2), along with the already reported stachybotrin I (3), stachybotrin H (4), stachybotrylactam (5), stachybotrylactam acetate (6), 2α-acetoxystachybotrylactam acetate (7), stachybotramide (8), chartarlactam B (9), and F1839-J (10) were isolated from the sponge-associated fungus Stachybotrys chartarum MUT 3308. Their structures were established based on extensive spectrometric (HRMS) and spectroscopic (1D and 2D NMR) analyses. Absolute configurations of the stereogenic centers of stachybotrin J (1), stachybocin G (2), and stachybotrin I (3), were determined by comparison of their experimental circular dichroism (CD) spectra with their time-dependent density functional theory (TD-DFT) circular dichroism (ECD) spectra. The putative structures of seventeen additional phenylspirodrimanes were proposed by analysis of their respective MS/MS spectra through a Feature-Based Molecular Networking approach. All the isolated compounds were evaluated for their cytotoxicity against five aggressive cancer cell lines (MP41, 786, 786R, CAL33, and CAL33RR), notably including two resistant human cancer cell lines (786R, CAL33RR), and compounds 5, 6, and 7 exhibited cytotoxicity with IC50 values in the range of 0.3-2.2 µM.

Novel Silver Complexes Based on Phosphanes and Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands Targeting TrxR: New Promising Chemotherapeutic Tools Relevant to SCLC Management

Bis(pyrazol-1-yl)acetic acid (HC(pz)2COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pzMe2)2COOH) were converted into the methyl ester derivatives 1 (LOMe) and 2 (L2OMe), respectively, and were used for the preparation of silver(I) complexes 3-5. The Ag(I) complexes were prepared by the reaction of AgNO3 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine (PPh3) with LOMe and L2OMe in methanol solution. All Ag(I) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in the in-house human cancer cell line panel containing examples of different solid tumors. Compounds were particularly effective against the highly aggressive and intrinsically resistant human small-cell lung carcinoma (SCLC) cells, either in 2D and 3D cancer cell models. Mechanistic studies revealed their ability to accumulate into cancer cells and to selectively target Thioredoxin (TrxR), thus leading to redox homeostasis unbalance and ultimately inducing cancer cell death through apoptosis.

GPX3 expression was down-regulated but positively correlated with poor outcome in human cancers.

Cancer is a crucial public health problem and one of the leading causes of death worldwide. Previous studies have suggested that GPX3 may be involved in cancer metastasis and chemotherapy resistance. However, how GPX3 affects cancer patients' outcomes and the underlying mechanism remains unclear. Sequencing data and clinical data from TCGA, GTEx, HPA, and CPTAC were used to explore the relationship between GPX3 expression and clinical features. Immunoinfiltration scores were used to assess the relationship between GPX3 and the tumor immune microenvironment. Functional enrichment analysis was used to predict the role of GPX3 in tumors. Gene mutation frequency, methylation level, and histone modification were used to predict the GPX3 expression regulation method. Breast, ovarian, colon, and gastric cancer cells were used to investigate the relationship between GPX3 expression and cancer cell metastasis, proliferation, and chemotherapy sensitivity. GPX3 is down-regulated in various tumor tissues, and GPX3 expression level can be used as a marker for cancer diagnosis. However, GPX3 expression is associated with higher stage and lymph node metastasis, as well as poorer prognosis. GPX3 is closely related to thyroid function and antioxidant function, and its expression may be regulated by epigenetic inheritance such as methylation modification or histone modification. In vitro experiments, GPX3 expression is associated with cancer cell sensitivity to oxidant and platinum-based chemotherapy and is involved in tumor metastasis in oxidative environments. We explored the relationship between GPX3 and clinical features, immune infiltration characteristics, migration and metastasis, and chemotherapy sensitivities of human cancers. We further investigated the potential genetic and epigenetic regulation of GPX3 in cancer. Our results suggested that GPX3 plays a complicated role in the tumor microenvironment, simultaneously promoting metastasis and chemotherapy resistance in human cancers.

Elevated PAF1-RAD52 axis confers chemoresistance to human cancers.

Cisplatin- and gemcitabine-based chemotherapeutics represent a mainstay of cancer therapy for most solid tumors; however, resistance limits their curative potential. Here, we identify RNA polymerase II-associated factor 1 (PAF1) as a common driver of cisplatin and gemcitabine resistance in human cancers (ovarian, lung, and pancreas). Mechanistically, cisplatin- and gemcitabine-resistant cells show enhanced DNA repair, which is inhibited by PAF1 silencing. We demonstrate an increased interaction of PAF1 with RAD52 in resistant cells. Targeting the PAF1 and RAD52 axis combined with cisplatin or gemcitabine strongly diminishes the survival potential of resistant cells. Overall, this study shows clinical evidence that the expression of PAF1 contributes to chemotherapy resistance and worse clinical outcome for lethal cancers.

Lycorine Carbamate Derivatives for Reversing P-glycoprotein-Mediated Multidrug Resistance in Human Colon Adenocarcinoma Cells.

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (1), a major Amaryllidaceae alkaloid isolated from Pancratium maritimum, was derivatized. Thirty-one new compounds (2-32) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds 1-32 were evaluated as MDR reversers, through the rhodamine-123 accumulation assay by flow cytometry and chemosensitivity assays, in resistant human colon adenocarcinoma cancer cells (Colo 320), overexpressing P-glycoprotein (P-gp, ABCB1). Significant inhibition of P-gp efflux activity was observed for the di-carbamate derivatives, mainly those containing aromatic substituents, at non-cytotoxic concentrations. Compound 5, bearing a benzyl substituent, and compounds 9 and 25, with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 µM, being more active than verapamil at 10-fold higher concentration. In drug combination assays, most compounds were able to synergize doxorubicin. Moreover, some derivatives showed a selective antiproliferative effect toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds (2, 5, 9, 19, 25, and 26) were shown to behave as inhibitors.

E3 Ubiquitin Ligase TRIP12 Controls Exit from Mitosis via Positive Regulation of MCL-1 in Response to Taxol.

Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (FBW7) mutations leads to the accumulation of its substrate MCL-1 which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase TRIP12 is a negative regulator of FBW7 protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by TRIP12 via its positive regulation of MCL-1 protein. Genetic inhibition of TRIP12 accelerates MCL-1 protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of FBW7 to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of MCL-1 protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, TRIP12 deletion leads to enhanced mitotic arrest and cell death in an FBW7 and MCL-1 dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the TRIP12/FBW7/MCL-1 axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer.