Around a million people are diagnosed with non-small cell lung cancer (NSCLC) worldwide each year and 85% of them will die during next 5 years. In spite of considerable efforts to improve the diagnostics and efficiency of treatment, the changes in mortality rate for the last couple decades is less than 2%. New effective approaches for anti-cancer therapy are hindered by the lack of knowledge of the mechanisms of lung carcinogenesis and a predictive strategy for efficient treatment. Among the genes dysregulated in NSCLC mutations in p53 and LKB1 are major traits, and their critical effect on lung carcinogenesis is supported by many mouse models. P53 suppresses carcinogenesis through transcriptional regulation of a number of genes, although the critical targets involved in tumor suppression are unknown. The LKB1 kinase phosphorylates and activates AMPK leading to inhibition of mTOR kinase, critical regulator of cell growth, proliferation and metabolism, which i activated in many lung cancers. Strikingly, similar to LKB1 p53 inhibits mTOR through activation of AMPK, although the inter-relation between p53- and LKB1-regulated signaling pathways is not well characterized. Recently we described a novel Sestrin (Sesn) gene family of stress-responsive genes in which expression is regulated in a p53-dependent manner. Sesns inhibit mTOR through AMPK regulation causing inhibition of cell growth and proliferation, activation of autophagy and protection against oxidative damage. Sesn1 and Sesn2 are downregulated in most human lung cancers and this leads to dysregulation of tumor growth and angiogenesis, so the Sesns are potential tumor suppressors and effectors of p53. The objective of the proposed work is to establish the importance of Sesn1 and Sesn2 in suppression of lung carcinogenesis and the outcome of anticancer treatment. To accomplish that we set up the following specific aims:
Aim 1 : To determine tumor suppressor properties of Sesn1 and Sesn2. We will apply of mouse model of K-ras-induced lung carcinogenesis and study whether inactivation or overexpression of Sesns modulate lung carcinogenesis. We will address the potential mechanisms, which involve regulation of cell proliferation and cell death, oxidative stress, autophagy and metabolism.
Aim 2 : To study the impact of the AMPK-mTOR pathway in regulation of carcinogenesis by Sesn1/2. We will analyze the role of Sesn1/2 in regulation of the AMPK-mTOR pathway in lung tissue and cancers and study whether the modulation of this pathway affects tumor-suppression function of Sesns.
Aim 3 : To understand the role of Sesn1/2 in anticancer treatment. We will treat Sesn1/2-deficient and proficient tumors and cancer cells with irradiation and DNA-damaging drugs and determine the impact of Sesn1/2 in tumor growth, cell viability and proliferation. The accomplishment of these goals let us to understand the mechanisms of tumor suppression in lung and design the more advanced approaches to diagnose and treat lung cancers decreasing the enormous death toll.

Public Health Relevance

The proposed research is relevant to public health because lung cancer is diagnosed in more than 1,2 million patients per annum, with ~1 million death/year and the 5year survival rate is less than 15%. For the last couple decades there is only a small improvement in the survival rate making lung cancer the leading cause of cancer-related death. The major obstacle is a lack of knowledge of the mechanisms of lung carcinogenesis which preclude the development of new approaches for diagnosis and treatment of lung cancer. The project is relevant to NIH's mission because it lets us better understand the mechanisms of lung carcinogenesis and develop new approaches for anti-cancer treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Watson, Joanna M
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Virginia Commonwealth University
Schools of Medicine
United States
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Morrison, Alex; Chen, Li; Wang, Jinli et al. (2015) Sestrin2 promotes LKB1-mediated AMPK activation in the ischemic heart. FASEB J 29:408-17
Zhao, Baozhong; Shah, Palak; Budanov, Andrei V et al. (2014) Sestrin2 protein positively regulates AKT enzyme signaling and survival in human squamous cell carcinoma and melanoma cells. J Biol Chem 289:35806-14
Parmigiani, Anita; Nourbakhsh, Aida; Ding, Boxiao et al. (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9:1281-91
Budanov, Andrei V (2014) The role of tumor suppressor p53 in the antioxidant defense and metabolism. Subcell Biochem 85:337-58