Your browser doesn't support javascript.
loading
High dose isoleucine stabilizes nuclear PTEN to suppress the proliferation of lung cancer.
Wang, Haiqing; Chen, Sen; Kang, Wenhui; Ding, Bojiao; Cui, Shulan; Zhou, Li; Zhang, Na; Luo, Huiying; Wang, Mingjuan; Zhang, Fan; Zhao, Zezhou; Guo, Zihu; Wang, Chao; Li, Liang; Wang, Zhengzhong; Chen, Xuetong; Wang, Yonghua.
Afiliação
  • Wang H; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Chen S; Immune Cells and Antibody Engineering Research Center in University of Guizhou Province, Key Laboratory of Biology and Medical Engineering, School of Biology and Engineering (School of Modern Industry for Health and Medicine), Guizhou Medical University, Guiyang, 550025, China.
  • Kang W; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Ding B; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Cui S; School of Traditional Chinese Medicine, Baoji Vocational Technology College, Baoji, 721000, Shaanxi, China.
  • Zhou L; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Zhang N; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Luo H; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Wang M; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Zhang F; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China.
  • Zhao Z; Collaborative Innovation Center of Qiyao in Mt. Qinling, Yangling, 712100, Shaanxi, China.
  • Guo Z; College of Pharmacy, Heze University, Heze, 274015, Shandong, China.
  • Wang C; State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Parmaceutical Co. Ltd., Lianyungang, 222002, Jiangsu, China.
  • Li L; State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Parmaceutical Co. Ltd., Lianyungang, 222002, Jiangsu, China.
  • Wang Z; State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Parmaceutical Co. Ltd., Lianyungang, 222002, Jiangsu, China.
  • Chen X; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China. xuetongchen@nwu.edu.cn.
  • Wang Y; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, 710069, Shaanxi, China. yhwang@nwu.edu.cn.
Discov Oncol ; 14(1): 25, 2023 Feb 23.
Article em En | MEDLINE | ID: mdl-36820928
ABSTRACT

PURPOSE:

Cancer cells require a supply of amino acids, particularly essential amino acids such as branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine), to meet the increased nutrient demands of malignant tumors. The cell-autonomous and non-autonomous roles of altered BCAA supply have been implicated in cancer progression. The critical proteins involved in BCAA uptake, transport, metabolism, etc. serve as potential therapeutic biomarkers in human cancers. Here, we summarize the potential anti-tumor mechanism of BCAA by exploring the chain reaction triggered by increased BCAA supply in the tumor.

METHOD:

A system-wide strategy was employed to provide a generic solution to establish the links between BCAA and cancer based on comprehensive omics, molecular experimentation, and data analysis.

RESULTS:

BCAA over-supplementation (900 mg/kg) significantly inhibited tumor growth and reduced tumor burden, with isoleucine having the most pronounced effect. Surprisingly, isoleucine inhibited tumor growth independently of mTORC1 activation, a classical amino acid sensor. Exploratory transcriptome analysis revealed that Phosphatase and tensin homolog (PTEN) is the critical factor in the anti-tumor effect of isoleucine. By inhibiting PTEN ubiquitination, isoleucine can promote PTEN nuclear import and maintain PTEN nuclear stability. Interestingly, this process was regulated by isoleucine-tRNA ligase, cytoplasmic (IARS), a direct target of isoleucine. We demonstrated the enhanced interaction between IARS and PTEN in the presence of excess isoleucine. At the same time, IARS knockout leads to loss of isoleucine tumor suppressor ability.

CONCLUSION:

Overall, our results provide insights into the regulation of the IARS-PTEN anti-tumor axis by isoleucine and reveal a unique therapeutic approach based on enhancing cellular isoleucine supply.
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Discov Oncol Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Discov Oncol Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China