Update on Chemoresistance Mechanisms to First-Line Chemotherapy for Gallbladder Cancer and Potential Reversal Strategies.

OBJECTIVE: Gallbladder cancer (GBC) mortality remains high and chemoresistance is increasing. This review consolidates what is known about the mechanisms of chemoresistance to inform and accelerate the development of novel GBC-specific chemotherapies. METHODS: Studies related to GBC-related chemoresistance were systematically screened in PubMed using the advanced search function. Search terms included GBC, chemotherapy, and signaling pathway. RESULTS: Analysis of existing studies showed that GBC has poor sensitivity to cisplatin, gemcitabine (GEM), and 5-fluorouracil. DNA damage repair-related proteins, including CHK1, V-SCR, and H2AX, are involved in tumor adaptation to drugs. GBC-specific chemoresistance is often accompanied by changes in the apoptosis and autophagy-related molecules, BCL-2, CRT, and GBCDRlnc1. CD44 + and CD133 + GBC cells are less resistant to GEM, indicating that tumor stem cells are also involved in chemoresistance. In addition, glucose metabolism, fat synthesis, and glutathione metabolism can influence the development of drug resistance. Finally, chemosensitizers such as lovastatin, tamoxifen, chloroquine, and verapamil are able improve the therapeutic effect of cisplatin or GEM in GBC. CONCLUSIONS: This review summarizes recent experimental and clinical studies of the molecular mechanisms of chemoresistance, including autophagy, DNA damage, tumor stem cells, mitochondrial function, and metabolism, in GBC. Information on potential chemosensitizers is also discussed. The proposed strategies to reverse chemoresistance should inform the clinical use of chemosensitizers and gene-based targeted therapy for this disease.

OLFM4 depletion sensitizes gallbladder cancer cells to cisplatin through the ARL6IP1/caspase-3 axis.

BACKGROUND: Gallbladder cancer (GBC) is a highly lethal malignancy that carries an extremely poor prognosis due to its chemoresistant nature. Cisplatin (CDDP) is a first-line chemotherapeutic for GBC; however, patients experienced no benefit when treated with CDDP alone. The underlying mechanisms of CDDP resistance in GBC remain largely unknown. METHODS: Agilent mRNA microarray analysis was performed between paired GBC and paracarcinoma to explore differentially expressed genes that might underlie drug resistance. Gene Set Enrichment Analysis (GSEA) was employed to identify key genes mediating CDDP resistance in GBC, and immunohistochemistry was performed to validate protein expression and test correlations with clinicopathological features. In vitro and in vivo functional assays were performed to investigate the proteins' roles in CDDP resistance. RESULTS: Olfactomedin 4 (OLFM4) was differentially expressed between GBC and paracarcinoma and had the highest rank metric score in the GSEA. OLFM4 expression was increasingly upregulated from chronic cholecystitis to GBC in clinical tissue samples, and OLFM4 depletion decreased GBC cell proliferation and invasion. Interestingly, downregulation of OLFM4 reduced ARL6IP1 (antiapoptotic factor) expression and sensitized GBC cells to CDDP both in vitro and in vivo. The evidence indicated that CDDP could significantly increase Bax and Bad expression and activate caspase-3 cascade in OLFM4-depleted GBC cells through ARL6IP1. Clinically, lower OLFM4 expression was associated with good prognosis of GBC patients. CONCLUSIONS: Our results suggest that OLFM4 is an essential gene that contributes to GBC chemoresistance and could serve as a prognostic biomarker for GBC. Importantly, OLFM4 could be a potential chemotherapeutic target.