p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis

Abstract

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.

Mitochondrial localization of SESN2

“…Furthermore, while it was reported that AKAP1 is capable of stimulating the activity of mTORC1, and SESN2 can counteract its effect, we were not able to observe any notable difference in the mTORC1 activity between control and SESN1-and/or SESN2-deficient cells incubated under standard cell culture conditions. These data indicate no negative effects of SESN1 and SESN2 on the mTORC1 activity despite the proposed role of AKAP1 in this process [35,36]. We also demonstrated that while SESN2 does not affect GATOR2 localization on the mitochondria, GATOR2 facilitated mitochondrial localization of SESN2, supporting the idea that AKAP1 is probably dispensable for this process (Figs 3 and 4).…”

“…To determine whether SESN2 interacts with Mios on the mitochondria, we immunoprecipitated endogenous SESN2 from mitochondrial fraction using an anti-SESN2 antibody as previously described [20] and analyzed the presence of Mios in the SESN2 immunoprecipitates. As a negative control, we also analyzed mitochondrial lysates from the cells where SESN2 was knocked out with CRISPR/Cas9 [35]. While we were able to detect Mios in the immunoprecipitates from control cells, indicating that these proteins interact on mitochondria, we did not observe any presence of Mios as well as SESN2 protein in the immunoprecipitated samples from SESN2-deficient cells ( Fig 3A).…”

“…Still, the non-OXPHOS oxygen consumption in cSesn knockout animals was lower than in control animals, as indicated by the treatment with an inhibitor of mitochondrial OXPHOS sodium azide [41] confirming the effects of cSesn on mitochondrial respiration (Fig 6A-6C). To analyze whether SESN2 plays a role in the regulation of mitochondrial respiration in adenocarcinoma A549 cells, we analyzed the levels of basal and maximal respiration in control and SESN2 knockout cells where expression SESN2 was inactivated with two different sgRNA [42]. Inactivation of SESN2 notably decreases the basal respiration rate, the maximal respiration rate, and the respiration rate associated with ATP production in A549 cells indicating the important role of SESN2 in support mitochondrial activity in cancer and normal cells.…”

Sestrin2 Expression Has Regulatory Properties and Prognostic Value in Lung Cancer

“…Based on these results, we suggest that Sestrin2 has oncogenic effects in lung cancer cells. Consistently, lung cancer cells from Sestrin2-deficient mice showed slower growth rates than did those from wild type mice [38]. However, Sestrin2 knockdown has also been reported to promote proliferation of cancer cells, inhibit apoptosis of cells [38][39][40], and enhance migration in the wound healing assay [40], which is in complete contrast to our results.…”

“…Consistently, lung cancer cells from Sestrin2-deficient mice showed slower growth rates than did those from wild type mice [38]. However, Sestrin2 knockdown has also been reported to promote proliferation of cancer cells, inhibit apoptosis of cells [38][39][40], and enhance migration in the wound healing assay [40], which is in complete contrast to our results. Several previous studies have reported that Sestrin2 can work as a tumor suppressor gene in various cancers [20][21][22].…”