SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline

Abstract

BackgroundBarely 10-20% of patients with metastatic colorectal cancer (mCRC) receive a clinical benefit from the use of anti-EGFR monoclonal antibodies (mAbs). We hypothesized that this could depends on their efficiency to reduce Store Operated Calcium Entry (SOCE) that are known to enhance cancer cells.ResultsIn the present study, we demonstrate that SOCE promotes migration of colon cancer cell following the formation of a lipid raft ion channel complex composed of TRPC1/Orai1 and SK3 channels. Formation of this complex is stimulated by the phosphorylation of the reticular protein STIM1 by EGF and activation of the Akt pathway. Our data show that, in a positive feedback loop SOCE activates both Akt pathway and SK3 channel activity which lead to SOCE amplification. This amplification occurs through the activation of Rac1/Calpain mediated by Akt. We also show that Anti-EGFR mAbs can modulate SOCE and cancer cell migration through the Akt pathway. Interestingly, the alkyl-lipid Ohmline, which we previously showed to be an inhibitor of SK3 channel, can dissociated the lipid raft ion channel complex through decreased phosphorylation of Akt and modulation of mAbs action.ConclusionsThis study demonstrates that the inhibition of the SOCE-dependent colon cancer cell migration trough SK3/TRPC1/Orai1 channel complex by the alkyl-lipid Ohmline may be a novel strategy to modulate Anti-EGFR mAb action in mCRC.

TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces

“…This rather contentious puzzle was resolved by studies showing that store depletion initiates the assembly of TRPC1 into a Ca 2+ signaling complex containing Orai1 and STIM1 that is localized within ER-PM junctions. This has now been demonstrated in HSG cells [57], human parathyroid cells [65], human liver cells [66], human colon cancer cells [67], mouse pulmonary arterial smooth muscle cells [68, 69], rat kidney fibroblasts [70], rat insulinoma cells [71] and mouse acinar cells from the pancreas and salivary glands [26, 72]. Further, the assembly of the TRPC1/Orai1/STIM1 complex is dependent on the clustering of STIM1 in ER-PM junctions and eliminated by knockdown of STIM1.…”

The store-operated calcium channels in cancer metastasis from cell migration invasion to metastatic colonization

“…Strikingly, stimulation of SOCE by ectopic expression of STIM1 together with Orai1 was able to confer human mammary epithelial cells MCF-10A with ability to invade Matrigel, suggesting that activation of SOCE in non-invasive epithelial cells with invasiveness (16). In the last several years, there is rapidly accumulating evidence supporting the pro-migration and pro-invasion activity of SOCE in a variety of cancers, including breast cancer (32–39), cervical cancer(40–42), hepatocellular carcinoma (43–45), renal carcinoma(46, 47), nasopharyngeal carcinoma (48), glioblastoma (49, 50), colorectal cancer (51–55) and melanoma(56–60). In this section we will discuss the molecular mechanisms by which SOCE promotes cancer cell migration and invasion.…”

“…Mechanistically, SOCE regulates focal adhesion turnover through small GTPase, Ras and Rac (Figure 1). Increase in cytosolic Ca2 + activates Ras/Rac, and ectopic expression of constitutively active Ras and Rac is able to rescue focal adhesion turnover and cell migration defects after SOCE inhibition (16, 55). Several Ras and Rac GEFs (e.g.…”

“…Calpain contains several Ca2 + -binding motifs in its catalytic and regulatory subunits. Ca2 + binding is required for calpain activation (79), and SOCE blockade inhibits its activity in cervical and colon cancer cells (40, 55). The proteolytic processing of some focal adhesion proteins, such as talin, paxillin, FAK, is a rate-limiting step in focal adhesion disassembly (79–82).…”

“…It has been reported in luminal breast cancer that SPCA2 is able to activate Orai1 in a STIM1 and ER Ca2 + store-independent manner to promote tumor growth (32). Another example of store-independent activation of Orai1 is the SK3-Orai1 complex in breast cancer and colon cancer models (39, 55). It is reported that SK3 potassium channel forms complex with Orai1 in the plasma membrane lipid rafts to activate Orai1 through plasma membrane hyperpolarization (39).…”