Résumé
Background and Purpose: Gastrointestinal tumours overexpress voltage-gated calcium (Ca(V)3) channels (Ca(V)3.1, 3.2 and 3.3). Ca(V)3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits Ca(V)3 currents. A systematic study was performed on gossypol blocking mechanism on Ca(V)3 channels and its potential anticancer effects in colon cancer cells, which express Ca(V)3 isoforms. Experimental Approach: Transcripts for Ca(V)3 proteins were analysed in gastrointestinal cancers using public repositories and in human colorectal cancer cell lines HCT116, SW480 and SW620. The gossypol blocking mechanism on Ca(V)3 channels was investigated by combining heterologous expression systems and patch-clamp experiments. The anti-tumoural properties of gossypol were estimated by cell proliferation, viability and cell cycle assays. Ca2+ dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca2+ indicators. Key Results: High levels of Ca(V)3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of Ca(V)3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of Ca(V)3 channels. Gossypol and Ca(V)3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G(0)/G(1) and G(2)/M phases, respectively. Ca(V)3 channels underlie the vectorial Ca2+ uptake by endoplasmic reticulum in colorectal cancer cells. Conclusion and Implications: Gossypol differentially blocked Ca(V)3 channel and its anticancer activity was correlated with high levels of Ca(V)3.1 and Ca(V)3.2 in colorectal cancer cells. The Ca(V)3 regulates cell proliferation and Ca2+ dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.