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| 題名: | PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer |
| 作者: | 范世榮;Fan, S-J;Snell, C;Turley, H;Li, J-L;McCormick, R;Perera, S M W;Heublein, S;Kazi, S;Azad, A;Wilson, C;Harris, A L;Goberdhan, D C I |
| 貢獻者: | 生醫理工學院生命科學系 |
| 關鍵詞: | 13/105;13/106;14/19;38/109;38/44;38/89;631/67/327;82/29;82/80;96/1;96/63;Amino Acid Transport Systems - biosynthesis;Amino Acid Transport Systems - metabolism;Amino acids;Amino Acids - metabolism;Animals;Apoptosis;Care and treatment;Carrier proteins;Cell Biology;Clinical outcomes;Colorectal cancer;Colorectal Neoplasms - drug therapy;Colorectal Neoplasms - genetics;Colorectal Neoplasms - metabolism;Development and progression;Drug Resistance, Neoplasm;Female;Gene expression;Genetic aspects;Golgi Apparatus - metabolism;HCT116 Cells;Health aspects;Human Genetics;Humans;Internal Medicine;Mechanistic Target of Rapamycin Complex 1;Medicine;Medicine & Public Health;Mice;Mice, Inbred BALB C;Mice, Nude;Mice, SCID;Multiprotein Complexes - metabolism;Nutrients;Oncology;Original;original-article;Patient outcomes;Properties;Signal Transduction;Sirolimus - pharmacology;TOR Serine-Threonine Kinases - metabolism;Treatment Outcome;Tumors |
| 日期: | 2016-06-09 |
| 上傳時間: | 2026-04-23 11:13:35 (UTC+8) |
| 出版者: | Nature Publishing Group;London: Springer Science and Business Media LLC |
| 摘要: | 摘要： Tumour cells can use strategies that make them resistant to nutrient deprivation to outcompete their neighbours. A key integrator of the cell’s responses to starvation and other stresses is amino-acid-dependent mechanistic target of rapamycin complex 1 (mTORC1). Activation of mTORC1 on late endosomes and lysosomes is facilitated by amino-acid transporters within the solute-linked carrier 36 (SLC36) and SLC38 families. Here, we analyse the functions of SLC36 family member, SLC36A4, otherwise known as p roton-assisted a mino-acid t ransporter 4 (PAT4), in colorectal cancer. We show that independent of other major pathological factors, high PAT4 expression is associated with reduced relapse-free survival after colorectal cancer surgery. Consistent with this, PAT4 promotes HCT116 human colorectal cancer cell proliferation in culture and tumour growth in xenograft models. Inducible knockdown in HCT116 cells reveals that PAT4 regulates a form of mTORC1 with two distinct properties: first, it preferentially targets eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and second, it is resistant to rapamycin treatment. Furthermore, in HCT116 cells two non-essential amino acids, glutamine and serine, which are often rapidly metabolised by tumour cells, regulate rapamycin-resistant mTORC1 in a PAT4-dependent manner. Overexpressed PAT4 is also able to promote rapamycin resistance in human embryonic kidney-293 cells. PAT4 is predominantly associated with the Golgi apparatus in a range of cell types, and in situ proximity ligation analysis shows that PAT4 interacts with both mTORC1 and its regulator Rab1A on the Golgi. These findings, together with other studies, suggest that differentially localised intracellular amino-acid transporters contribute to the activation of alternate forms of mTORC1. Furthermore, our data predict that colorectal cancer cells with high PAT4 expression will be more resistant to depletion of serine and glutamine, allowing them to survive and outgrow neighbouring normal and tumorigenic cells, and potentially providing a new route for pharmacological intervention.
其他題名： Oncogene
出版者： London: Springer Science and Business Media LLC
出版日期： 2016-06-09
出處： Oncogene, 2016-06, Vol.35 (23), p.3004-3015
資源來源： Springer Nature OA Free Journals
版權： The Author(s) 2016
版權： COPYRIGHT 2016 Nature Publishing Group
版權： Copyright Nature Publishing Group Jun 9, 2016
版權： Copyright © 2016 Macmillan Publishers Limited 2016 Macmillan Publishers Limited
識別號： ISSN: 0950-9232
識別號： ISSN: 1476-5594
識別號： EISSN: 1476-5594
識別號： DOI: 10.1038/onc.2015.363
識別號： PMID: 26434594
識別號： CODEN: ONCNES |
| 顯示於類別: | [生命科學系] 期刊論文
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