Abstract
AbstractTransmembrane 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.
Funder
National Research Foundation of Korea
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference65 articles.
1. Chae, H. J. et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol. Cell15, 355–366 (2004).
2. Xu, Q. & Reed, J. C. Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol. Cell1, 337–346 (1998).
3. Zhou, J. et al. Comparative genomics and function analysis on BI1 family. Comput. Biol. Chem.32, 159–162 (2008).
4. Grzmil, M. et al. Expression and functional analysis of Bax inhibitor-1 in human breast cancer cells. J. Pathol.208, 340–349 (2006).
5. Lu, B. et al. Bax inhibitor-1 is overexpressed in non-small cell lung cancer and promotes its progression and metastasis. Int J. Clin. Exp. Pathol.8, 1411–1418 (2015).
Cited by
38 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献