STAT3, IP3R3 and mTOR interplay in the regulation of calcium homeostasis and apoptosis in breast cancer

Signal transducer and activator of transcription 3 (STAT3) is a pleiotropic transcription factor that is often constitutively activated in tumors. Among its largely characterized antiapoptotic functions, the ability to control ER Ca2+ release, thus reducing Ca2+-mediated apoptosis, was recently described. We have previously reported that STAT3 can localize to the Endoplasmic Reticulum (ER) and Mitochondrial Associated Membranes (MAMs), where it interacts with the Ca2+ channel IP3R3. Moreover, having determined that STAT3 silencing caused an increase of IP3R3 levels, we discovered that serine-phosphorylated STAT3 can trigger IP3R3 degradation in STAT3-dependent tumor cells, since the use of a serine non-phosphorylatable STAT3 mutant fails to down-regulate IP3R3 levels. Accordingly, the highly aggressive human basal-like breast tumors, which frequently display constitutively activated STAT3, show an inverse correlation between IP3R3-STAT3 protein levels. To further dissect this mechanism, we searched for known STAT3 interactors reported to localize to the ER, and selected the mammalian target of rapamycin (mTOR) as the most promising target. First of all, we confirmed the STAT3-mTOR interaction in human triple negative breast cancer and melanoma cells. Further, we demonstrated that pharmacological mTOR inhibition can prevent STAT3-dependent IP3R3 degradation. Under these conditions, mTOR acts as a late kinase triggering STAT3 serine phosphorylation, while ERK, another kinase implicated in STAT3 serine phosphorylation, acts as the early kinase. Further studies, shedding light on the role of the kinases interplay in the activation of ER STAT3 and inhibition of apoptosis, may reveal novel targeted approaches disrupting apoptotic resistance in STAT3-dependent tumor cells.