한빛사 논문
Hyun-Kyoung Kim1, Kashi Raj Bhattarai1, Raghu Patil Junjappa1, Jin Hee Ahn2, Suvarna H. Pagire2, Hyun Ju Yoo3, Jaeseok Han4, Duckgue Lee4, Kyung-Woon Kim5, Hyung-Ryong Kim6,* & Han-Jung Chae1,*
1Department of Pharmacology and New Drug Development Research Institute, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea.
2Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
3Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
4Soonchunhyang Institute of Med-bio Science (SIMS), Sooncynhyang University, Cheonan-si 31151, Republic of Korea.
5Animal Biotechnology Division, National Institute of Animal Science, Rural Development Administration (RDA), Wanju-gun, Jeonbuk 54875, Republic of Korea.
6College of Dentistry, Dankook University, Cheonan 31116, Republic of Korea.
*Corresponding author
Abstract
Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly up-regulated in several cancer types. Here, we show that TMBIM6 is closely associated with survival in patients with cervical, breast, lung, and prostate cancer. TMBIM6 deletion or knockdown suppresses primary tumor growth. Further, mTORC2 activation is up-regulated by TMBIM6 and stimulates glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, is shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identify that the BIA compound, a potentialTMBIM6 antagonist, prevents TMBIM6 binding to mTORC2, decreases mTORC2 activity, and also regulates TMBIM6-leaky Ca2+, further suppressing tumor formation and progression in cancer xenograft models. This previously unknown signaling cascade in which mTORC2 activity is enhanced via the interaction with TMBIM6 provides potential therapeutic targets for various malignancies.
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