Blockade of Ca3 calcium channels and induction of G/G cell cycle arrest in colon cancer cells by gossypol.

BACKGROUND AND PURPOSE

Gastrointestinal tumours overexpress voltage-gated calcium (Ca3) channels (Ca3.1, 3.2 and 3.3). Ca3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits Ca3 currents. A systematic study was performed on gossypol blocking mechanism on Ca3 channels and its potential anticancer effects in colon cancer cells, which express Ca3 isoforms.

EXPERIMENTAL APPROACH

Transcripts for Ca3 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 Ca3 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. Ca dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca indicators.

KEY RESULTS

High levels of Ca3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of Ca3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of Ca3 channels. Gossypol and Ca3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G/G and G/M phases, respectively. Ca3 channels underlie the vectorial Ca uptake by endoplasmic reticulum in colorectal cancer cells.

CONCLUSION AND IMPLICATIONS

Gossypol differentially blocked Ca3 channel and its anticancer activity was correlated with high levels of Ca3.1 and Ca3.2 in colorectal cancer cells. The Ca3 regulates cell proliferation and Ca dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.