Selective Vulnerability of Cancer Cells by Inhibition of Ca2+ Transfer from Endoplasmic Reticulum to Mitochondria

•Low-level ER-to-mitochondria Ca2+ flux maintains ATP levels in cells•Absence of basal mitochondrial Ca2+ uptake induces autophagy•Autophagy protects normal cells but is insufficient for survival of cancer cells•Cancer cells fundamentally require basal mitochondrial Ca2+ uptake for survival

SummaryIn the absence of low-level ER-to-mitochondrial Ca2+ transfer, ATP levels fall, and AMPK-dependent, mTOR-independent autophagy is induced as an essential survival mechanism in many cell types. Here, we demonstrate that tumorigenic cancer cell lines, transformed primary human fibroblasts, and tumors in vivo respond similarly but that autophagy is insufficient for survival, and cancer cells die while their normal counterparts are spared. Cancer cell death is due to compromised bioenergetics that can be rescued with metabolic substrates or nucleotides and caused by necrosis associated with mitotic catastrophe during their proliferation. Our findings reveal an unexpected dependency on constitutive Ca2+ transfer to mitochondria for viability of tumorigenic cells and suggest that mitochondrial Ca2+ addiction is a feature of cancer cells.

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