Kakumoto Kyoko, Ikeda Jun-Ichiro, Okada Masato, Morii Eiichi, Oneyama Chitose
Department of Oncogene Research, Research Institute for Microbial Disease, Osaka, University, Suita, Osaka, Japan.
Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
PLoS One. 2015 Apr 23;10(4):e0119015. doi: 10.1371/journal.pone.0119015. eCollection 2015.
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.
雷帕霉素作用机制靶点（mTOR）的活性在多种人类癌症中升高，这表明其在肿瘤进展中发挥作用。然而，mTOR上调背后的分子机制仍不清楚。在本研究中，我们发现mTOR复合物1（mTORC1）和复合物2（mTORC2）的必需亚基mLST8在几种人类结肠和前列腺癌细胞系及组织中表达上调。敲低mLST8可显著抑制mTORC1和mTORC2复合物的形成，还能抑制人结肠癌（HCT116）和前列腺癌（LNCaP）细胞的肿瘤生长和侵袭性。mLST8的过表达诱导正常上皮细胞（HaCaT）形成不依赖贴壁的细胞生长，尽管敲低mLST8对正常细胞生长没有影响。敲低mLST8可降低癌细胞和正常细胞中mTORC2介导的AKT磷酸化，而它在癌细胞中能有效抑制mTORC1介导的4E-BP1磷酸化。这些结果表明，mLST8根据其表达水平在正常细胞和癌细胞中发挥不同作用，且mLST8上调可能通过持续激活mTORC1和mTORC2途径促进肿瘤进展。
