Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis

The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53’s control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis. DOI: http://dx.doi.org/10.7554/eLife.12204.001

[1]  D. Sabatini,et al.  Sestrin2 is a leucine sensor for the mTORC1 pathway , 2016, Science.

[2]  Seung-Hyun Ro,et al.  Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains , 2015, Nature Communications.

[3]  C. Thompson,et al.  GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2 , 2015, Genes & development.

[4]  S. Agarwal,et al.  p53 Deletion or Hotspot Mutations Enhance mTORC1 Activity by Altering Lysosomal Dynamics of TSC2 and Rheb , 2015, Molecular Cancer Research.

[5]  A. Budanov,et al.  Sestrin2 facilitates death receptor-induced apoptosis in lung adenocarcinoma cells through regulation of XIAP degradation , 2015, Cell cycle.

[6]  M. Karin,et al.  Sestrin2 inhibits mTORC1 through modulation of GATOR complexes , 2015, Scientific Reports.

[7]  Michael N. Hall,et al.  mTORC1 mediated translational elongation limits intestinal tumour initiation and growth , 2014, Nature.

[8]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[9]  Wei Wang,et al.  Sestrins inhibit mTORC1 kinase activation through the GATOR complex. , 2014, Cell reports.

[10]  Steven P Gygi,et al.  The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. , 2014, Cell reports.

[11]  Ming O. Li,et al.  Sestrins Function as Guanine Nucleotide Dissociation Inhibitors for Rag GTPases to Control mTORC1 Signaling , 2014, Cell.

[12]  Myungjin Kim,et al.  Sestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1 , 2014, The FEBS journal.

[13]  R. Kaufman,et al.  The impact of the endoplasmic reticulum protein-folding environment on cancer development , 2014, Nature Reviews Cancer.

[14]  Myungjin Kim,et al.  Hepatoprotective role of Sestrin2 against chronic ER stress , 2014, Nature Communications.

[15]  P. Einat,et al.  Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species , 2014, Proceedings of the National Academy of Sciences.

[16]  E. Fearon,et al.  Rapamycin Inhibition of Polyposis and Progression to Dysplasia in a Mouse Model , 2014, PloS one.

[17]  M. Karin,et al.  Sestrins orchestrate cellular metabolism to attenuate aging. , 2013, Cell metabolism.

[18]  K. Friese,et al.  Nelfinavir and bortezomib inhibit mTOR activity via ATF4‐mediated sestrin‐2 regulation , 2013, Molecular oncology.

[19]  S. Rivella,et al.  Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia , 2013, Proceedings of the National Academy of Sciences.

[20]  J. Greenson,et al.  Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice. , 2013, Gastroenterology.

[21]  J. Hurley,et al.  The molecular genetics of colorectal cancer , 2013, Frontline Gastroenterology.

[22]  Kathleen R. Cho,et al.  Sox9 induction, ectopic Paneth cells, and mitotic spindle axis defects in mouse colon adenomatous epithelium arising from conditional biallelic Apc inactivation. , 2013, The American journal of pathology.

[23]  A. Mancuso,et al.  Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. , 2013, Genes & development.

[24]  R. Kaufman,et al.  The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice. , 2013, Gastroenterology.

[25]  M. Hallek,et al.  mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. , 2013, The Journal of clinical investigation.

[26]  Hye Eun Lee,et al.  Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. , 2013, Cell metabolism.

[27]  C. Datz,et al.  Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth , 2012, Nature.

[28]  Mark Ellisman,et al.  Maintenance of metabolic homeostasis by Sestrin2 and Sestrin3. , 2012, Cell metabolism.

[29]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[30]  Hong Zhu,et al.  Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence , 2012, Experimental biology and medicine.

[31]  T. Tsakiridis,et al.  Sestrin2 Modulates AMPK Subunit Expression and Its Response to Ionizing Radiation in Breast Cancer Cells , 2012, PloS one.

[32]  B. Vainer,et al.  Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis , 2011, Nature Reviews Gastroenterology &Hepatology.

[33]  E. Fearon.  Molecular genetics of colorectal cancer. , 2011, Annual review of pathology.

[34]  A. Kaser,et al.  Crohn's disease: NOD2, autophagy and ER stress converge , 2011, Gut.

[35]  D. Sabatini,et al.  mTOR: from growth signal integration to cancer, diabetes and ageing , 2010, Nature Reviews Molecular Cell Biology.

[36]  M. Skrzypczak,et al.  Correction: Modeling Oncogenic Signaling in Colon Tumors by Multidirectional Analyses of Microarray Data Directed for Maximization of Analytical Reliability , 2010, PLoS ONE.

[37]  Krzysztof Goryca,et al.  Modeling Oncogenic Signaling in Colon Tumors by Multidirectional Analyses of Microarray Data Directed for Maximization of Analytical Reliability , 2010, PloS one.

[38]  A. Levine,et al.  The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. , 2010, Trends in cell biology.

[39]  Michael Karin,et al.  Inflammation and colon cancer. , 2010, Gastroenterology.

[40]  Mark H. Ellisman,et al.  Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies , 2010, Science.

[41]  Thomas Downey,et al.  A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics , 2010, Clinical & Experimental Metastasis.

[42]  Jun Hee Lee,et al.  Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression , 2010, Cell.

[43]  S. Rhee,et al.  Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxins. , 2009, Antioxidants and Redox Signaling.

[44]  Charles Giardina,et al.  Mouse models for the study of colon carcinogenesis. , 2008, Carcinogenesis.

[45]  Michael Karin,et al.  p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling , 2009, Cell.

[46]  N. Hay,et al.  Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. , 2008, Cancer cell.

[47]  H. Tilg,et al.  XBP1 Links ER Stress to Intestinal Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease , 2008, Cell.

[48]  Eduardo Sontag,et al.  Transcriptional control of human p53-regulated genes , 2008, Nature Reviews Molecular Cell Biology.

[49]  H. Morreau,et al.  Cross-species comparison of human and mouse intestinal polyps reveals conserved mechanisms in adenomatous polyposis coli (APC)-driven tumorigenesis. , 2008, The American journal of pathology.

[50]  M. Sahin,et al.  Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. , 2008, Molecular cell.

[51]  A. Levine,et al.  The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. , 2007, Cancer research.

[52]  T. Barrette,et al.  Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. , 2007, Neoplasia.

[53]  T. Yeatman,et al.  Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer , 2007, Genome Biology.

[54]  Charles Auffray,et al.  Deciphering cellular states of innate tumor drug responses , 2006, Genome Biology.

[55]  P. Chumakov,et al.  The antioxidant function of the p53 tumor suppressor , 2005, Nature Medicine.

[56]  Xiao-Jun Ma,et al.  Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer , 2004, Cancer Research.

[57]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[58]  K. Wakabayashi,et al.  Gene mutations and altered gene expression in azoxymethane‐induced colon carcinogenesis in rodents , 2004, Cancer science.

[59]  E. Koonin,et al.  Regeneration of Peroxiredoxins by p53-Regulated Sestrins, Homologs of Bacterial AhpD , 2004, Science.

[60]  A. Chajut,et al.  Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability , 2002, Oncogene.

[61]  Judy H. Cho,et al.  Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. , 2001, The Journal of clinical investigation.

[62]  Leonard Buckbinder,et al.  PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes , 1999, Oncogene.

[63]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.