Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells

Abstract

Gastric cancer (GC) is characterized by poor efficacy and modest clinical impact of current therapies, in which apoptosis evasion is relevant. Intracellular calcium homeostasis dysregulation is associated with apoptosis escaping, and aberrant expression of calcium regulator genes could promote GC drug resistance. Since we previously found a prognostic value for TRPV2 calcium channel expression in GC, we aimed to characterize the role of TRPV2 in cisplatin resistance. Using the TCGA-STAD dataset, we performed a differential gene expression analysis between GC samples in upper and lower tertiles of TRPV2 expression, and then through a gene set analysis, we highlighted the enriched ontology and canonical pathways. We used qRT-PCR to assess TRPV2 expression in three GC cell lines and flow cytometry to evaluate cisplatin-induced cell death rates. Calcium green-1-AM assay was used to estimate differences in intracellular Ca2+ concentrations after inhibition of TRPV2. We engineered AGS cell line to overexpress TRPV2 and used confocal microscopy to quantify its overexpression and localization and flow cytometry to evaluate their sensitivity to cisplatin. Consistent with our hypothesis, among enriched gene sets, we found a significant number of those involved in the regulation of apoptosis. Subsequently, we found an inverse correlation between TRPV2 expression and sensitivity to cisplatin in GC cell lines. Moreover, we demonstrated that inhibition of TRPV2 activity by tranilast blocks the efflux of Ca2+ ions and, in combination with cisplatin, induced a significant increase of apoptotic cells (p = 0.004). We also demonstrated that TRPV2 exogenous expression confers a drug-resistant phenotype, and that tranilast is able to revert this phenotype, restoring cisplatin sensitivity. Our findings consistently suggested that TRPV2 could be a potential target for overcoming cisplatin resistance by promoting apoptosis. Notably, our data are a prerequisite for the potential reposition of tranilast to the treatment of GC patients and anticipate the in vivo evaluation.

Dihydrophenanthrenes from a Sicilian Accession of Himantoglossum robertianum (Loisel.) P. Delforge Showed Antioxidant, Antimicrobial, and Antiproliferative Activities

“…The assay confirmed the high sensitivity of AGS cells that showed a significant decrease in live cells for both compounds as compared to KATO-III cells. Interestingly, this finding reflects the drug resistant phenotype described in other reports [60,61].…”

A TRP Family Based Signature for Prognosis Prediction in Head and Neck Squamous Cell Carcinoma

“…For instance, alteration of the TRPV2 expression level was proven to be a prognostic factor for multiple myeloma cases [ 29 ]. Also, TRPV2 overexpression confers a drug-resistant phenotype in gastric cancer, suggesting that promoting tumor cell apoptosis by targeting TRPV2 may be a potential treatment for overcoming drug resistance [ 30 ].…”

Thermo-Transient Receptor Potential Channels: Therapeutic Potential in Gastric Cancer

“…However, currently only TRPV2, TRPV4 and TRPV5 are identified as having a vital role in the development of GC. The expression of TRPV2 has been reported to be negatively correlated with the survival of GC patients [ 36 , 37 ]. Chemical inhibition of TRPV2 significantly augments cisplatin-induced death of GC cells, whereas overexpression of TRPV2 in GC cells weakens the killing effect of cisplatin.…”

“…Chemical inhibition of TRPV2 significantly augments cisplatin-induced death of GC cells, whereas overexpression of TRPV2 in GC cells weakens the killing effect of cisplatin. This uncovers the potential of TRPV2 as a therapeutic target for GC progression, and blockade of TRPV2 in combination with chemotherapeutic agents may boost the treatment efficacy for GC patients [ 37 ]. TRPV5 and TRPV6 comprise a distinct subfamily of homomeric and heteromeric channels found in transporting epithelia of the kidney and intestine [ 38 ].…”