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.
Highlights
The mammalian target of rapamycin is a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family. mTOR assembles into two large protein complexes, mTOR complex 1 and mTOR complex 2, which are independently regulated by distinct binding partners [1,2,3,4]. mTORC1 contains RAPTOR and PRAS40, while mTORC2 contains RICTOR, mSIN1, and PROTOR. mTORC1 is activated by diverse stimuli such as nutrients and growth factors and by the PI3K–AKT pathway, and the complex controls cell growth by regulating protein synthesis via phosphorylation of its downstream substrates, ribosomal S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) [5, 6]
We addressed the role of mammalian lethal with SEC13 protein 8 (mLST8), a requisite component of mTOR complexes, in tumor progression
We found that mLST8 is upregulated in some human cancer tissues and cells, and that upregulated mLST8 promotes mTORC1/2 formation and induces activation of AKT and phosphorylation of 4E-BP1, resulting in promotion of tumor growth as well as invasive potential of cancer cells
Summary
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family. mTOR assembles into two large protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are independently regulated by distinct binding partners [1,2,3,4]. mTORC1 contains RAPTOR and PRAS40, while mTORC2 contains RICTOR, mSIN1, and PROTOR. mTORC1 is activated by diverse stimuli such as nutrients and growth factors and by the PI3K–AKT pathway, and the complex controls cell growth by regulating protein synthesis via phosphorylation of its downstream substrates, ribosomal S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) [5, 6]. MLST8 Promotes Tumor Progression cytoskeleton by activating AKT, protein kinase C-α (PKC-α), and serum- and glucocorticoidinduced protein kinase 1 (SGK-1) [7, 8] Both mTOR pathways are frequently deregulated in human cancers. Recent work has shown that various cancer cells have elevated mTOR activity due to upregulation of mTOR complex components, e.g., mTOR, RICTOR, RAPTOR, mSIN1, PRAS40, and DEPTOR [9,10,11,12,13,14]. Mutation of mTOR itself contributes to the risk of various cancers [16,17,18,19] Based on these findings, the mTOR pathway is regarded as a promising therapeutic target for some human cancers; specific inhibitors of mTOR complexes, such as rapamycin analogs (Rapalogs) and mTOR kinase inhibitors, are being actively developed [20, 21]
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