TY - JOUR
T1 - Double C-2 like domain beta (DOC2B) induces calcium dependent oxidative stress to promote lipotoxicity and mitochondrial dysfunction for its tumor suppressive function
AU - Adiga, Divya
AU - Bhat, Samatha
AU - Shukla, Vaibhav
AU - Shah, Henil Vinit
AU - Kuthethur, Raviprasad
AU - Chakrabarty, Sanjiban
AU - Kabekkodu, Shama Prasada
N1 - Funding Information:
The study was supported by DBT, Government of India, under the pilot project on cancer (Sanction number: 6242-P8/RGCB/PMD/DBT/SPDK/2015).We acknowledge Dr. TMA Pai Structured Ph.D. fellowship program of MAHE, and senior research fellowship from ICMR (Reference ID: 2019/4115/CMB/BMS), Government of India, for financial assistance. All the authors thank Manipal Academy of Higher Education, Manipal, Technology Information Forecasting and Assessment Council (TIFAC)- Core in Pharmacogenomics at MAHE, Manipal, Fund for Improvement of S&T Infrastructure (FIST), and Karnataka Fund for Infrastructure Strengthening in Science and Technology (K-FIST), Government of Karnataka, and Builder Grant, Department of Biotechnology, Government of India.
Funding Information:
We acknowledge Dr. TMA Pai Structured Ph.D. fellowship program of MAHE, and senior research fellowship from ICMR (Reference ID: 2019/4115/CMB/BMS), Government of India, for financial assistance. All the authors thank Manipal Academy of Higher Education, Manipal , Technology Information Forecasting and Assessment Council (TIFAC) - Core in Pharmacogenomics at MAHE, Manipal, Fund for Improvement of S&T Infrastructure (FIST) , and Karnataka Fund for Infrastructure Strengthening in Science and Technology (K-FIST) , Government of Karnataka, and Builder Grant, Department of Biotechnology, Government of India.
Publisher Copyright:
© 2023 Elsevier Inc.
PY - 2023/5/20
Y1 - 2023/5/20
N2 - 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.
AB - 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.
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U2 - 10.1016/j.freeradbiomed.2023.03.010
DO - 10.1016/j.freeradbiomed.2023.03.010
M3 - Article
AN - SCOPUS:85149862981
SN - 0891-5849
VL - 201
SP - 1
EP - 13
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -