Calcium signaling and T-type calcium channels in cancer cell cycling

Abstract

Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca 2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca 2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel is minimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca 2+ channels are not expressed in epithelial cells, selective T-type Ca 2+ channel blockers may be useful in the treatment of certain types of cancers.

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

“…Many studies have been conducted to evaluate how the regulatory system of intracellular calcium homeostasis and the associated calcium signaling pathways are altered in breast cancer cells compared with normal mammary gland cells. A recent review summarizes the possible roles of T-type calcium channels in breast cancer progression (30). The essential roles of the SOCC Orai1 and the signaling molecule Stim1 in breast cancer metastasis formation was recently reported (31).…”

Molecular discrimination of cutaneous squamous cell carcinoma from actinic keratosis and normal skin

“…27 The mechanisms of the deregulation of calcium signaling have been shown through T-type calcium channels, calcium pumps/exchangers, vitamin D, and calcium-sensing receptors. [27][28][29][30][31][32][33] Calcium and vitamin D pathways have been found to be especially important in activating the genetic pathways required for keratinocyte differentiation. 34,35 Bikle et al 35 showed that squamous cell carcinoma cell lines failed to respond to the prodifferentiating actions of vitamin D. Alterations of calcium signaling have also been linked to carcinomas of breast, colon, esophagus, liver, ovarian, and prostate origin.…”

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

“…In addition, an antagonist selective for T-type Ca 2þ channels, mibefradil, has been proposed recently as a sensitizing agent with activity in vivo in combination with chemo-(9) or radiotherapy (10). Aberrant expression of T-type Ca 2þ channels in cancer cells is thought to promote cell survival, proliferation, and motility (3,11); however, the molecular mechanisms for these effects are poorly understood.…”