p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis
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Boxiao Ding3,*, Alexander Haidurov1,2,*, Ayesha Chawla5, Anita Parmigiani3, Gerarda van de Kamp2, Alexandra Dalina1, Fang Yuan4, Jun Hee Lee7, Peter M. Chumakov1, Steven R. Grossman3,4,6 and Andrei V. Budanov1,2,3
1 Engelhardt Institute of Molecular Biology, Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Moscow, Russia
2 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
3 Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
4 Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
5 Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, USA
6 VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
7 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
* These authors contributed equally to this work
|Andrei V. Budanov,||email:||firstname.lastname@example.org|
Keywords: SESTRINs; lung cancer; mouse model; mTORC1/2; tumor suppression
Abbreviations: mTORC1/2: mammalian target of rapamycin complex 1/2; ROS: reactive oxygen species; NSCLC: non-small cell lung cancer
Received: September 03, 2019 Accepted: November 17, 2019 Published: December 10, 2019
SESTRINs (SESN1-3) are proteins encoded by an evolutionarily conserved gene family that plays an important role in the regulation of cell viability and metabolism in response to stress. Many of the effects of SESTRINs are mediated by negative and positive regulation of mechanistic target of rapamycin kinase complexes 1 and 2 (mTORC1 and mTORC2), respectively, that are often deregulated in human cancers where they support cell growth, proliferation, and cell viability. Besides their effects on regulation of mTORC1/2, SESTRINs also control the accumulation of reactive oxygen species, cell death, and mitophagy. SESN1 and SESN2 are transcriptional targets of tumor suppressor protein p53 and may mediate tumor suppressor activities of p53. Therefore, we conducted studies based on a mouse lung cancer model and human lung adenocarcinoma A549 cells to evaluate the potential impact of SESN1 and SESN2 on lung carcinogenesis. While we observed that expression of SESN1 and SESN2 is often decreased in human tumors, inactivation of Sesn2 in mice positively regulates tumor growth through a mechanism associated with activation of AKT, while knockout of Sesn1 has no additional impact on carcinogenesis in Sesn2-deficient mice. However, inactivation of SESN1 and/or SESN2 in A549 cells accelerates cell proliferation and imparts resistance to cell death in response to glucose starvation. We propose that despite their contribution to early tumor growth, SESTRINs might suppress late stages of carcinogenesis through inhibition of cell proliferation or activation of cell death in conditions of nutrient deficiency.
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