Abstract
STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcriptional activator and as a non-canonical regulator of energy metabolism and mitochondrial functions. While both activities are required for cell transformation downstream of different oncogenic stimuli, they rely on different post-translational activating events, namely phosphorylation on either Y705 (nuclear activities) or S727 (mitochondrial functions). Here, we report the discovery of the unexpected STAT3 localization to the endoplasmic reticulum (ER), from where it modulates ER-mitochondria Ca2+ release by interacting with the Ca2+ channel IP3R3 and facilitating its degradation. The release of Ca2+ is of paramount importance for life/death cell decisions, as excessive Ca2+ causes mitochondrial Ca2+ overload, the opening of the mitochondrial permeability transition pore, and the initiation of the intrinsic apoptotic program. Indeed, STAT3 silencing enhances ER Ca2+ release and sensitivity to apoptosis following oxidative stress in STAT3-dependent mammary tumor cells, correlating with increased IP3R3 levels. Accordingly, basal-like mammary tumors, which frequently display constitutively active STAT3, show an inverse correlation between IP3R3 and STAT3 protein levels. These results suggest that STAT3-mediated IP3R3 downregulation in the ER crucially contributes to its anti-apoptotic functions via modulation of Ca2+ fluxes.
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Acknowledgements
The authors wish to thank M. Brancaccio, J. Clohessy, M. Martini, E. Monteleone, and P. Porporato for critically reading the manuscript, and S. Rocca, G. Carrà , and L. Conti for help with FACS analysis. This work was supported by grants from the Italian Association for Cancer Research (AIRC IG16930), the San Paolo Foundation, the Italian Ministry for Education, University and Research (MIUR PRIN) and the Truus and Gerrit van Riemsdijk Foundation, Liechtenstein, to VP, the Italian Ministry of Education, University and Research, the Italian Ministry of Health, Telethon (GGP15219/B), the Italian Association for Cancer Research (IG-18624) and the University of Ferrara to PP, and the Italian Association for Cancer Research, the Italian Ministry of Health, the Cariplo Foundation and the University of Ferrara to CG. LA was the recipient of an Italian Cancer Research Foundation (FIRC) post-doctoral fellowship. AC was the recipient of a Fondazione Veronesi post-doctoral fellowship.
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Avalle, L., Camporeale, A., Morciano, G. et al. STAT3 localizes to the ER, acting as a gatekeeper for ER-mitochondrion Ca2+ fluxes and apoptotic responses. Cell Death Differ 26, 932–942 (2019). https://doi.org/10.1038/s41418-018-0171-y
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DOI: https://doi.org/10.1038/s41418-018-0171-y
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