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.