2. Academic Validation
  3. TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

  • Nat Commun. 2020 Aug 11;11(1):4012. doi: 10.1038/s41467-020-17802-4.
Hyun-Kyoung Kim 1,  Kashi Raj Bhattarai 1,  Raghu Patil Junjappa 1,  Jin Hee Ahn 2,  Suvarna H Pagire 2,  Hyun Ju Yoo 3,  Jaeseok Han 4,  Duckgue Lee 4,  Kyung-Woon Kim 5,  Hyung-Ryong Kim 6,  Han-Jung Chae 7
Affiliations

Affiliations

  • 1 Department of Pharmacology and New Drug Development Research Institute, Jeonbuk National University Medical School, Jeonju, 54896, Republic of Korea.
  • 2 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
  • 3 Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
  • 4 Soonchunhyang Institute of Med-bio Science (SIMS), Sooncynhyang University, Cheonan-si, 31151, Republic of Korea.
  • 5 Animal Biotechnology Division, National Institute of Animal Science, Rural Development Administration (RDA), Wanju-gun, Jeonbuk, 54875, Republic of Korea.
  • 6 College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea. hrkimdp@gmail.com.
  • 7 Department of Pharmacology and New Drug Development Research Institute, Jeonbuk National University Medical School, Jeonju, 54896, Republic of Korea. hjchae@jbnu.ac.kr.
PMID: 32782388 DOI: 10.1038/s41467-020-17802-4
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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