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

• Published in: Nature communications Vol. 11; no. 1; pp. 4012 - 16
• Main Authors: Kim, Hyun-Kyoung, Bhattarai, Kashi Raj, Junjappa, Raghu Patil, Ahn, Jin Hee, Pagire, Suvarna H., Yoo, Hyun Ju, Han, Jaeseok, Lee, Duckgue, Kim, Kyung-Woon, Kim, Hyung-Ryong, Chae, Han-Jung
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/1; 38/109; 38/23; 38/61; 38/70; 38/77; 38/88; 631/67/1059/153; 631/67/2327; 64/116; 64/60; AKT protein; Animals; Anticancer properties; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Assembly; Bcl-2 protein; Breast cancer; Calcium; Calcium - metabolism; Calcium ions; Cancer; Cell activation; Cell Line, Tumor; Cell Transformation, Neoplastic - drug effects; Cervix; Endoplasmic Reticulum - metabolism; Gene expression; Glycolysis; Humanities and Social Sciences; Humans; Indenes - pharmacology; Lipids; Lung cancer; Lymphoma; Mechanistic Target of Rapamycin Complex 2 - metabolism; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; multidisciplinary; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Prostate cancer; Protein Binding; Protein biosynthesis; Protein synthesis; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Ribosomes; Ribosomes - metabolism; Science; Science (multidisciplinary); Signal Transduction; Survival Analysis; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17802-4

Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca 2+ 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 Ca 2+ 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 Ca 2+ , 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. TMBIM6, a member of the transmembrane BI-1 motif-containing family of proteins, is overexpressed in many cancer types. Here, the authors show that TMBIM6 regulates AKT activation through mTORC2 assembly and ribosome association and identify an antagonist of TMBIM6 with anti-tumor properties.