Cancer Cell Survival Following DNA Damage-mediated Premature Senescence Is Regulated by Mammalian Target of Rapamycin (mTOR)-dependent Inhibition of Sirtuin 1

Abstract

Cellular senescence is a state of permanent replicative arrest that is linked to telomere erosion and dysfunction that engages at least two mechanisms, the p53 and the p16INK4a -pRB pathways (1, 2). In cancer cells, the presence of oncogenic mutations, chemotherapeutic drugs, and oxidative stress can cause an acutely inducible, telomere-independent, stress-responsive form of cellular senescence, termed premature senescence (PS) 2 (3, 4). PS is considered a physiologic mechanism of DNA damage response occurring in chemotherapy (5-7), and the senescence induction could be an effective in vivo mechanism to limit tumor progression by preventing cancer cell proliferation or by blocking the cells at risk of neoplastic transformation (8). However, the physiological consequences of prematurely induced senescent (PIS) cancer cells remain elusive. PIS cancer cells have been shown to promote the growth of neighboring cells, and they are intrinsically resistant to chemotherapeutic agents (5, 9, 10). Importantly, cells in prematurely senescent tumors are capable of escaping growth arrest and re-entering the cell cycle, leading to tumor relapse (5, 9, 11). As for the mechanism underlying escape from DNA damage-induced senescence, overexpression of the cyclin-dependent kinase Cdc2 has been found in clones that bypassed replicative arrest in human non-small cell H1299 carcinoma (5) and in MCF-7 breast cancer cells (9). It was recently shown that survivin is the immediate downstream effector of Cdc2/Cdk1 and that phosphorylated survivin is necessary for the escape of senescent cells (12). Moreover, Twist1, which is involved in the metastatic dissemination of cancer cells, was shown to override oncogeneinduced senescence by abrogating cell cycle inhibition by p21 and p16 (11, 13), leading to complete epithelial-mesenchymal transition and implicating a direct link between escape from senescence and the acquisition of invasive features by cancer (11, 13). These data collectively suggest that there exist mechanisms that foster survival of PIS cancer cells and promote escape of these cells from the senescent state, which are likely detrimental to the overall therapeutic efficacy of cancer treatment. Because the p53 gene is frequently inactivated in 50% of * This work was supported, in whole or in part, by National Institutes of Health Grants R01 ES015323 (to M. A.) and K01-AR048582 and R03 CA125855 (to A. L. K.). This work was also supported by an Irving Scholar Award and Skin Cancer Foundation grant (to A. L. K. 2 The abbreviations used are: PS, premature senescence; PIS, prematurely induced senescent; ATM, ataxia telangiectasia, mutated; ATR, ATM and Rad3-related; Bfl-1/A1, Bcl2-related protein A1; Chk1/2, checkpoint kinase 1/2; DOX, doxorubicin; DYRK, the dual specificity, tyrosine phosphorylation-regulated kinase; MBP, maltose-binding protein; mTOR, mammalian target of rapamycin; mTORC1, the rapamycin-sensitive mTOR complex

SIRT1 Limits the Function and Fate of Myeloid-Derived Suppressor Cells in Tumors by Orchestrating HIF-1α–Dependent Glycolysis

“…SIRT1 has shown negative regulatory effects on mTOR (49,50). In our report, SIRT1 deficiency in MDSCs after LPS stimulation could significantly upregulate p-S6 expression, a downstream target molecule of mTOR.…”

Cyclin-Dependent Kinase 5–Mediated Hyperphosphorylation of Sirtuin-1 Contributes to the Development of Endothelial Senescence and Atherosclerosis

“…The phosphorylation is associated with the induction of premature senescence in A431 cells and can be cross-regulated by mammalian target of rapamycin signaling pathway. 40 In colon cancer cells, c-Jun N-terminal kinase-2 (JNK2), but not JNK1, is positively associated with the occurrence of S47 phosphorylation. 41 In HEK293 cells, oxidative stress promotes the interactions between SIRT1 and JNK1, but an in vitro phosphorylation assay suggests that JNK1 stimulates phosphorylation of truncated human SIRT1 that lacks the region containing S47.…”

The N-Terminal Domain of SIRT1 Is a Positive Regulator of Endogenous SIRT1-Dependent Deacetylation and Transcriptional Outputs

“…Additionally, several protein regulators of SIRT1 have been identified, including the positive regulators AROS ( a ctive r egulator o f S IRT1) and Necdin (Hasegawa, 2008; Kim et al, 2008) and an inhibitory protein DBC1 ( d eleted in b reast c ancer 1) (Kim et al, 2008; Zhao et al, 2008). SIRT1 is phosphorylated at multiple sites, and some of these posttranslational modifications alter interactions with proteins that are deacetylated by SIRT1 (Back et al, 2011; Kang et al, 2009; Nasrin et al, 2009; Nin et al, 2012). Additionally, methylation, sumoylation and nitrosylation of SIRT1 have been reported (Revollo and Li, 2013), although the functional significance and mechanisms of these modifications are not fully understood.…”