Double C-2 like domain beta (DOC2B) induces calcium dependent oxidative stress to promote lipotoxicity and mitochondrial dysfunction for its tumor suppressive function

Abstract

Mitochondria are biosynthetic and bioenergetic organelles that regulate many biological processes, including metabolism, oxidative stress, and cell death. Cervical cancer (CC) cells show impairments in mitochondrial structure and function and are linked with cancer progression. DOC2B is a tumor suppressor with anti-proliferative, anti-migratory, anti-invasive, and anti-metastatic function in CC. For the first time, we demonstrated the role of the DOC2B-mitochondrial axis with tumor growth regulatory functions in CC. We used DOC2B overexpression and knockdown model systems to show that DOC2B is localized to mitochondria and induces Ca²⁺-mediated lipotoxicity. DOC2B expression induced mitochondrial morphological changes with the subsequent reduction in mitochondrial DNA copy number, mitochondrial mass, and mitochondrial membrane potential. Intracellular and mitochondrial Ca²⁺, intracellular O^.-₂, and ATP levels were substantially elevated in the presence of DOC2B. DOC2B manipulation reduced glucose uptake, lactate production, and mitochondrial complex-IV activity. The presence of DOC2B significantly reduced the proteins associated with mitochondrial structure and biogenesis with the concomitant activation of AMPK signaling. Augmented lipid peroxidation (LPO) in the presence of DOC2B was a Ca²⁺-dependent process. Our findings demonstrated that DOC2B promotes lipid accumulation, oxidative stress, and LPO through intracellular Ca²⁺ overload, which may contribute to mitochondrial dysfunction and tumor-suppressive properties of DOC2B. We propose that the DOC2B-Ca²⁺-oxidative stress-LPO-mitochondrial axis could be targeted for confining CC. Further, the induction of lipotoxicity in tumor cells by activating DOC2B could serve as a novel therapeutic approach in CC.

Keywords: Calcium; DOC2B; Lipotoxicity; Mitochondrial dysfunction; Senescence.