mLST8 Promotes mTOR-Mediated Tumor Progression

Abstract

The activity of the mechanistic target of rapamycin (mTOR) is elevated in various types of human cancers, implicating a role in tumor progression. However, the molecular mechanisms underlying mTOR upregulation remain unclear. In this study, we found that the expression of mLST8, a required subunit of both mTOR complex 1 (mTORC1) and complex 2 (mTORC2), was upregulated in several human colon and prostate cancer cell lines and tissues. Knockdown of mLST8 significantly suppressed mTORC1 and mTORC2 complex formation, and it also inhibited tumor growth and invasiveness in human colon carcinoma (HCT116) and prostate cancer (LNCaP) cells. Overexpression of mLST8 induced anchorage-independent cell growth in normal epithelial cells (HaCaT), although mLST8 knockdown had no effect on normal cell growth. mLST8 knockdown reduced mTORC2-mediated phosphorylation of AKT in both cancer and normal cells, whereas it potently inhibited mTORC1-mediated phosphorylation of 4E-BP1 specifically in cancer cells. These results suggest that mLST8 plays distinct roles in normal and cancer cells, depending upon its expression level, and that mLST8 upregulation may contribute to tumor progression by constitutively activating both the mTORC1 and mTORC2 pathways.

Comprehensive transcriptome analysis identifies pathways with therapeutic potential in locally advanced cervical cancer

“…Previously, it has been reported in prostate carcinomas and advanced ovarian cancer that SOS1 overexpression correlates with cancer progression and with a shorter survival, indicating that its dysregulation is an essential requirement for tumorigenesis [17]. We noticed that MLTS8/GBL mRNA and protein were overexpressed in CC, its expression has been evaluated in other tumors, such as prostate and colon cancer, and contributes to tumor growth and invasion; in addition, strong protein expression has been observed in invasive cancer lesions [18].…”

Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma

“…This contradiction may indicate a compensatory increase in mTOR transcription in response to inhibition of this pathway. However, the GEP data also showed that expression of Myotubularin-related protein 3 ( MTMR3 ), a negative mTOR complex 1 (mTORC1) regulator 43 , was increased, while that of mTOR-associated protein LST8 homolog ( MLST8 ), a required subunit and positive regulator of mTORC1 and mTORC2 44 , was decreased, supporting the possibility of mTOR inhibition. Moreover, these data are consistent with prior studies showing that BET inhibitors lowered phospho-inositide 3-kinase (PI3K) signaling, and dissociated BRD4 from chromatin at regulatory regions of the Insulin-like growth factor-1 receptor 35 .…”

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

“…Although enhanced mTOR signaling activation has been reported to not be associated with the survival of some tumor patients, targeting mTOR signaling is still a reasonable approach for tumor radiotherapy [33][34][35][36]. Any protein in the PI3K/AKT/mTOR pathway can be targeted for the clinical inhibition of mTOR activation in tumor tissues [37,38]. In particular, clinically targeting mTOR signaling during radiotherapy could increase tumor radiosensitivity [39].…”