The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca2+ homeostasis

Abstract

The remodeling of calcium homeostasis contributes to the cancer hallmarks and the molecular mechanisms involved in calcium channel regulation in tumors remain to be characterized. Here, we report that SigmaR1, a stress-activated chaperone, is required to increase calcium influx by triggering the coupling between SK3, a Ca-activated K channel (KCNN3) and the voltage-independent calcium channel Orai1. We show that SigmaR1 physically binds SK3 in BC cells. Inhibition of SigmaR1 activity, either by molecular silencing or by the use of sigma ligand (igmesine), decreased SK3 current and Ca entry in breast cancer (BC) and colorectal cancer (CRC) cells. Interestingly, SigmaR1 inhibition diminished SK3 and/or Orai1 levels in lipid nanodomains isolated from BC cells. Analyses of tissue microarray from CRC patients showed higher SigmaR1 expression levels in cancer samples and a correlation with tumor grade. Moreover, the exploration of a cohort of 4937 BC patients indicated that high expression of SigmaR1 and Orai1 channels was significantly correlated to a lower overall survival. As the SK3/Orai1 tandem drives invasive process in CRC and bone metastasis progression in BC, our results may inaugurate innovative therapeutic approaches targeting SigmaR1 to control the remodeling of Ca homeostasis in epithelial cancers.

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

“…In our model, we observed a clear reduction in both the tumor area and the number of tumor foci, associated with a decreased number of intratumoral myofibroblasts. Haloperidol was previously shown to inhibit tumor growth, possibly by binding to Sigmar1 expressed by various types of cancer cells (41,66), and repurposing of haloperidol as an anticancer drug has been proposed for the treatment of glioblastoma (67). As we did not detect any inhibitory effect of haloperidol on the proliferation of LG cells (data not shown), we believe that in our model the main mechanism by which it has reduced tumor growth in vivo was through the inhibition of myofibroblast activation.…”

Roles of endogenous ether lipids and associated PUFAs in the regulation of ion channels and their relevance for disease

“…These observations could explain the observed delocalization of SK3 and Orai1 channels outside cholesterol-enriched nanodomains leading to the decrease of SK3 activity (2). These results can lean on the fact that SK3 activity is sensitive not only to cholesterol content in pig and rat arteries but also in breast and colorectal cancer cells, where its activity is decreased by MβCD (34,211) and strongly associated with caveolin-rich domains (2,211). We hypothesize that the presence of many cholesterol recognition/interaction amino acid consensus sequence (CRAC) domains, allowing tight interactions with cholesterol, on SK3 protein sequences could explain its sensitivity to cholesterol.…”

“…This channel, which belongs to small conductance calcium-activated potassium channels, controls the small after-hyperpolarization phase and then the regulation of the frequency of action potential (33). The SK3 channel is sensitive to cholesterol content and membrane state (34). In fact, we reported the effect of 1-O-hexadecyl-2-O-methyl-sn-glycero-3-lactose (Ohmline), a synthetic EL, which inhibits SK3 channel activity by removing the cholesterol OH moieties away from their main binding sites, including the SK3 channel (3).…”

Mitochondrial Involvement in Migration, Invasion and Metastasis

“…When ER stress is not activated, Sig1R cooperates with MAMs chaperone BiP/GRP78, whereas under activation of IP3Rs Sig1R dissociates from chaperone BiP and binds to IP3R3, leading to its stabilization at the MAM and increasing Ca 2+ flux to the mitochondria (De Pinto and Palmieri, 1992;Naon and Scorrano, 2014). The expression level of MAM-associated Sig1R is increased in metastatic breast and colorectal cancer cells as compared to normal tissues (Gueguinou et al, 2017). Consistently with the abovementioned MAM-related proteins, MCU also affects migration, invasion and metastasis.…”