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This galley proof is being listed electronically before publishing the final manuscript (It's not final version).

Mitochondrial Dysfunction Induced by Callyspongiolide Promotes Autophagy-Dependent Cell Death
Soohyun Lee 1,2 (Research worker), Yoonjeong Jeong 1 (Research worker), Jae-Seok Roe2 (Professor), Hoyoung Huh1 (CEO), Sang Hoon Paik 1 (Head of Research Center), Jaewhan Song 1,2,* (Professor)
1Asia Research Center, pH Pharma Co., Ltd., B - 1009, U-Space 2, 670 Daewangpangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13494, Korea,
2Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Korea
Callyspongiolide is a marine macrolide known to induce caspase-independent cancer cell death. While its toxic effects have been known, the mechanism leading to cell death is yet to be identified. We report that Callyspongiolide R form at C-21 (cally2R) causes mitochondrial dysfunction by inhibiting-mitochondrial complex I or II, leading to a disruption of mitochondrial membrane potential and a deprivation of cellular energy. Subsequently, we observed, using electron microscopy, a drastic formation of autophagosome and mitophagy. Supporting these data, LC3, an autophagosome marker, was shown to co-localize with LAMP2, a lysosomal protein, showing autolysosome formation. RNA sequencing results indicated the induction of hypoxia and blocking of EGF-dependent pathways, which could be caused by induction of autophagy. Furthermore, mTOR and AKT pathways preventing autophagy were repressed while AMPK was upregulated, supporting autophagosome progress. Finally, the combination of cally2R with known anti-cancer drugs, such as gefitinib, sorafenib and rapamycin, led to synergistic cell death, implicating potential therapeutic applications of callyspongiolide for future treatments.
Abstract, Accepted Manuscript(in press) [Submitted on March 5, 2021, Accepted on April 1, 2021]
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