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

Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, a Ca2+ channel-like protein, is highly upregulated 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 suppressed primary tumor growth. Further, mTORC2 activation was up-regulated by TMBIM6 and stimulated glycolysis, protein synthesis, and the expression of lipid synthesis genes and glycosylated proteins. Moreover, ER-leaky Ca2+ from TMBIM6, a unique characteristic, was shown to affect mTORC2 assembly and its association with ribosomes. In addition, we identified that BIA compound, a suggestive TMBIM6 antagonist, prevented TMBIM6 binding to mTORC2, decreased mTORC2 activity, and also regulated 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 effective therapeutic targets for various malignancies. We used microarrays to detail the global of gene expression and identified that most of the differentially expressed genes related to apoptotic process, migration, proliferation, and metabolic pathways were decreased in TMBIM6 KO HT1080 cells Transcriptome profiling of TMBIM6 wild type and knock out HT1080 cells using Affymetrix GeneChip Human Gene 2.0 ST oligonucleotide Array. Two replicates of cells for each cell type were performed.