Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer

Dritschilo, 2011, Integrated analysis of ATM mediated gene and protein expression impacting cellular metabolism, J Proteome Res, 1, 2651

Costanzo, 2011, ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair, EMBO J, 3, 546

Ralser, 2011, ATM is a redox sensor linking genome stability and carbon metabolism, Sci Signal, 4, pe17

Tainer, 2011, All stressed out without ATM kinase, Sci Signal, 4, pe18

Cortez, 2009, Common mechanisms of PIKK regulation, DNA Repair (Amst), 8, 1004, 10.1016/j.dnarep.2009.04.006

Lavin, 2008, Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signaling and cancer, Nat Rev Mol Cell Biol, 9, 759, 10.1038/nrm2514

Yang, 2007, AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner, Mol Cell Biochem, 30, 239

Carr, 2011, Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes, Nat Genet, 4, 117

Qi, 2008, Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation, PLoS One, 3, e2009, 10.1371/journal.pone.0002009

Tsakiridis, 2010, Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells, Int J Radiat Oncol Biol Phys, 7, 221

Shaw, 2011, Genomics: Drugs, diabetes and cancer, Nature, 47, 338

Menendez, 2011, Metformin activates an Ataxia Telangiectasia Mutated (ATM)/Chk2-regulated DNA damage-like response, Cell Cycle, 1, 1499

Blagosklonny, 2009, Pseudo-DNAdamage response in senescent cells, Cell Cycle, 8, 4112, 10.4161/cc.8.24.10215

Elledge, 2000, Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro, Proc Natl Acad Sci U S A, 9, 10389

Tibbetts, 2004, Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress, Proc Natl Acad Sci U S A, 10, 5898

Tibbetts, 2006, DNA replication stress-induced phosphorylation of cyclic AMP response element-binding protein mediated by ATM, J Biol Chem, 28, 1692

Menendez, 2010, Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena, Cell Cycle, 9, 1057, 10.4161/cc.9.6.10994

Menendez, 2010, Metformin and energy metabolism in breast cancer: from insulin physiology to tumour-initiating stem cells, Curr Mol Med, 1, 674

Raes, 2002, CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation, EMBO J, 2, 53

Rucker, 2010, Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression, J Biol Chem, 28, 142

Papa, 2010, cAMP/Ca2+ response element-binding protein plays a central role in the biogenesis of respiratory chain proteins in mammalian cells, IUBMB Life, 6, 447

Kaplowitz, 2011, Role of cAMP-responsive element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3) in the initiation of mitochondrial biogenesis and stress response in liver cells, J Biol Chem, 28, 22047

de Cabo, 2008, Mitochondrial biogenesis and healthy aging, Exp Gerontol, 4, 813

Araki, 2006, Activation of AMP-activated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells, Diabetes, 5, 120

Kumagai, 2006, Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo, J Appl Physiol, 10, 1685

Chen, 2011, Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer cells by a novel AMPK activator, J Biol Chem

Thompson, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab, 7, 11, 10.1016/j.cmet.2007.10.002

Thompson, 2009, Tumor suppressors and cell metabolism: a recipe for cancer growth, Genes Dev, 2, 537

Thompson, 2009, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science, 32, 1029

Weinberg, 2011, Hallmarks of cancer: the next generation, Cell, 14, 646

Schnellmann, 2010, A high-throughput respirometric assay for mitochondrial biogenesis and toxicity, Anal Biochem, 40, 75

Rossignol, 2011, AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation, Biochim Biophys Acta, 180, 707

Scott, 2006, AMP-activated protein kinase: development of the energy sensor concept, J Physiol, 57, 7

Zarse, 2010, How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis), Exp Gerontol, 4, 410

Longo, 2009, Fasting and cancer treatment in humans: A case series report, Aging, 1, 988, 10.18632/aging.100114

Longo, 2010, Fasting and differential chemotherapy protection in patients, Cell Cycle, 9, 4474, 10.4161/cc.9.22.13954

Blagosklonny, 2011, Exploring long-term protection of normal human fibroblasts and epithelial cells from chemotherapy in cell culture, Oncotarget, 2, 222, 10.18632/oncotarget.248

Longo, 2011, Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients, Oncogene, 3, 3305

Darzynkiewicz, 2011, Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling, Aging, 3, 1028, 10.18632/aging.100397

Choubey, 2011, IFI16 induction by glucose restriction in human fibroblasts contributes to autophagy through activation of the ATM/AMPK/p53 pathway, PLoS One, 6, e19532, 10.1371/journal.pone.0019532

Thompson, 2007, Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth, Cancer Res, 6, 6745

Menendez, 2009, Autophagy facilitates the development of breast cancer resistance to the anti-HER2 monoclonal antibody trastuzumab, PLoS One, 4, e6251, 10.1371/journal.pone.0006251

de Lange, 1999, p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2, Science, 28, 1321

Jackson, 2003, DNA damage checkpoint response in telomere-initiated senescence, Nature, 42, 194

Brady, 2008, Ataxia telangiectasia mutated and p21CIP1 modulate cell survival of drug-induced senescent tumor cells: implications for chemotherapy, Clin Cancer Res, 1, 1877

Rusin, 2011, The activation of the p53 pathway by the AMP mimetic AICAR is reduced by inhibitors of the ATM or mTOR kinases, Mech Ageing Dev

Dirsch, 2007, Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells, J Biol Chem, 28, 26759

Campisi, 2005, Senescent cells, tumor supression, and organismal aging: good citizens, bad neighbors, Cell, 12, 513, 10.1016/j.cell.2005.02.003

Gorospe, 2003, Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function, J Biol Chem, 27, 27016

Jansen-Dürr, 2003, Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence, Biochem J, 37, 403

Shay, 2011, Cellular senescence as a tumor-protection mechanism: the essential role of counting, Curr Opin Genet Develop, 1, 98

Weinberg, 2004, When cells get stressed: an integrative view of cellular senescence, J Clin Invest, 11, 8

Beach, 2005, Glycolytic enzymes can modulate cellular life span, Cancer Res, 6, 177

Gil, 2007, Protection from oxidative stress by enhanced glycolysis; a possible mechanism of cellular immortalization, Histol Histopathol, 2, 85

Gil, 2008, A common metabolic profile shared between murine ES cells and primary cells bypassing senescence, Med Hypotheses Res, 4, 29

Kondoh, 2008, Cellular life span and the Warburg effect, Exp Cell Res, 31, 1923, 10.1016/j.yexcr.2008.03.007

Chainiaux, 2002, Stress-induced premature senescence or stress-induced senescence-like phenotype: one in vivo reality, two possible definitions?, Scientific World Journal, 2, 230, 10.1100/tsw.2002.100

von Zglinicki, 2001, BJ fibroblasts display high antioxidant capacity and slow telomere shortening independent of hTERT transfection, Free Radic Biol Med, 3, 824

Toussaint, 2002, Stress-induced premature senescence in BJ and hTERT-BJ1 human foreskin fibroblasts, FEBS Lett, 52, 157

Lees-Miller, 2004, 2004 Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species, J Biol Chem, 27, 53272

Holt, 2002, Adriamycin-induced senescence in breast tumor cells involves functional p53 and telomere dysfunction, J Biol Chem, 27, 35509

Hwang, 2005, Dinstinct ROS and biochemical profiles in cells undergoing DNA damage-induced senescence and apoptosis, Mech Ageing Dev, 12, 580

Gewirtz, 2009, Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to adriamycin, Biochem Pharmacol, 7, 1139

Sikora, 2009, Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells, Mech Ageing Dev, 13, 24

Yamanaka, 2006, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell, 12, 663

Gil, 2009, Senescence impairs successful reprogramming to pluripotent stem cells, Genes Dev, 2, 2134

Belmonte, 2009, Linking the p53 tumour suppressor pathway to somatic cell reprogramming, Nature, 46, 1140

Blasco, 2009, A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity, Nature, 46, 1149

d'Adda di Fagagna, 2006, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication, Nature, 44, 638

Li, 2010, Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation, Proc Natl Acad Sci U S A, 10, 3728

Wahl, 2002, c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability, Mol Cell, 9, 1031, 10.1016/S1097-2765(02)00520-8

Prochownik, 2005, Regulation of reactive oxygen species, DNA damage, and c-Myc function by peroxiredoxin 1, Oncogene, 2, 8038

Hochedlinger, 2009, Immortalization eliminates a roadblock during cellular reprogramming into iPS cells, Nature, 46, 1145

Yamanaka, 2009, Hypoxia enhances the generation of induced pluripotent stem cells, Cell Stem Cell, 5, 237, 10.1016/j.stem.2009.08.001

Gil, 2010, Induced pluripotent stem cells and senescence: learning the biology to improve the technology, EMBO Rep, 1, 353

Liu, 2010, Vitamin C enhances the generation of mouse and human induced pluripotent stem cells, Cell Stem Cell, 6, 71, 10.1016/j.stem.2009.12.001

Vazquez-Martin, 2011, mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: A roadmap from energy metabolism to stem cell renewal and aging, Cell Cycle, 1, 3658

He, 2011, miR-34 miRNAs provide a barrier for somatic cell reprogramming, Nat Cell Biol, 1, 1353

Stenius, 2001, Reduced ATM kinase activity and an attenuatedp53 response to DNA damage in carcinogen-induced preneoplastic hepatic lesions in the rat, Carcinogenesis, 2, 2023

Deng, 2006, ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency, EMBO J, 2, 2167

Krynetskiy, 2011, Accelerated cellular senescence phenotype of GAPDH-depleted human lung carcinoma cells, Biochem Biophys Res Commun, 41, 409

Choi, 2011, AMPK induces vascular smooth muscle cell senescence via LKB1 dependent pathway, Biochem Biophys Res Commun, 41, 143

Frevert, 2006, Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome, Cell Metab, 3, 403, 10.1016/j.cmet.2006.05.005

Carling, 2007, Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family, J Biol Chem, 28, 32539

Sakamoto, 2007, Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase, J Biol Chem, 28, 32549

Alessi, 2008, Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice, Biochem J, 41, 211

Adjaye, 2010, The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells, Stem Cells, 2, 721

Schatten, 2011, Energy metabolism in human pluripotent stem cells and their differentiated counterparts, PLoS One, 6, e20914, 10.1371/journal.pone.0020914

Terzic, 2011, Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming, Cell Metab, 1, 264

Belmonte, 2011, The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming, Cell Res

Chang, 2008, Module map of stem cell genes guides creation of epithelial cancer stem cells, Cell Stem Cell, 2, 333, 10.1016/j.stem.2008.02.009

Hardie, 2011, AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function, Genes Dev, 2, 1895, 10.1101/gad.17420111

Thompson, 2009, Histological evaluation of AMPKsignalling in primarybreast cancer, BMC Cancer, 9, 307, 10.1186/1471-2407-9-307

Menendez, 2009, AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor, Cell Cycle, 8, 3679, 10.4161/cc.8.22.9905

Struhl, 2009, Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission, Cancer Res, 6, 7507

Struhl, 2011, Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types, Cancer Res, 7, 3196

Menendez, 2011, The anti-diabetic drugmetforminsuppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells, Breast Cancer Res Treat, 12, 355

Menendez, 2010, Metforminagainst TGFβ-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis, Cell Cycle, 9, 4461, 10.4161/cc.9.22.14048

Menendez, 2010, Metforminregulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status, Cell Cycle, 9, 3807

Menendez, 2011, Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: induction of the tumor suppressor miRNA let-7a and suppression of the TGFβ-induced oncomiR miRNA-181a, Cell Cycle, 1, 1144

Menendez, 2011, Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions, Drug Resist Updat, 1, 212

Cobaleda, 2010, Physiological cellular reprogramming and cancer, Semin Cancer Biol, 2, 98

Bartek, 2005, DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis, Nature, 43, 864

Halazonetis, 2005, Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions, Nature, 43, 907

Serrano, 2005, The senescent side of tumor suppression, Cell Cycle, 4, 1722, 10.4161/cc.4.12.2260

Tlsty, 2007, Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors, Cancer Cell, 1, 479

Bhaumik, 2007, Two faces of p53: aging and tumor suppression, Nucleic Acids Res, 3, 7475

Kondoh, 2009, Senescence induction; a possible cancer therapy, Mol Cancer, 8, 3, 10.1186/1476-4598-8-3

Pandolfi, 2011, Pro-senescence therapy for cancer treatment, Nat Rev Cancer, 1, 503

Miller, 2007, Dynamic stromal-epithelial interactions during progression of MCF10DCIS.com xenografts, Int J Cancer, 12, 2127

Polyak, 2008, Regulation of in situ to invasive breast carcinoma transition, Cancer Cell, 1, 394

Medina, 2009, An intraductal human-in-mouse transplantation model mimics the subtypes of ductal carcinoma in situ, Breast Cancer Res, 1, R66

Lowe, 1997, Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a, Cell, 8, 593

Ferbeyre, 2007, The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence, Genes Dev, 2, 43

Lowe, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell, 13, 657

Rudolph, 2009, Keeping your senescent cells under control, Aging, 1, 438, 10.18632/aging.100046

Vucur, 2011, Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, Nature

Pollak, 2010, Metformin and other biguanides in oncology: advancing the research agenda, Cancer Prev Res (Phila), 3, 1060, 10.1158/1940-6207.CAPR-10-0175

Gonzalez-Angulo, 2009, Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer, J Clin Oncol, 2, 3297

Campisi, 2005, Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors, Cell, 12, 513, 10.1016/j.cell.2005.02.003

Campisi, 2008, Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor, PLoS Biol, 6, 2853

Campisi, 2011, Four faces of cellular senescence, J Cell Biol, 19, 547

Campisi, 2011, Cellular senescence: putting the paradoxes in perspective, Curr Opin Genet Dev, 2, 107, 10.1016/j.gde.2010.10.005

Peeper, 2010, The essence of senescence, Genes Dev, 2463

Lowe, 2005, Senescence comes of age, Nature Med, 1, 920

Campisi, 2001, Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging, Proc Natl Acad Sci U S A, 9, 12072

Lowe, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature, 44, 656

Melamed, 2008, Chemokine signaling via the CXCR2 receptor reinforces senescence, Cell, 13, 1006

Peeper, 2008, Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network, Cell, 13, 1019

Peeper, 2009, Senescence-messaging secretome: SMS-ing cellular stress, Nat Rev Cancer, 9, 81, 10.1038/nrc2560

d'Adda di Fagagna, 2009, SASPense and DDRama in cancer and ageing, Nat Cell Biol, 1, 921

van Deursen, 2011, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature, 47, 232

Franceschi, 2005, Effect ofmetforminon life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice, Exp Gerontol, 4, 685

Semenchenko, 2008, Metforminslows down aging and extends life span of female SHR mice, Cell Cycle, 7, 2769, 10.4161/cc.7.17.6625

Anisimov, 2010, Metforminfor aging and cancer prevention, Aging, 2, 760, 10.18632/aging.100230

Berstein, 2010, Gender differences inmetformineffect on aging, life span and spontaneous tumorigenesis in 129/Sv mice, Aging, 2, 945, 10.18632/aging.100245

Poroshina, 2011, If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice, Aging, 3, 148, 10.18632/aging.100273

Vazquez-Martin, 2011, Gerosuppressantmetformin: less is more, Aging, 3, 348, 10.18632/aging.100316

Aaronson, 2002, Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence, EMBO J, 2, 2180

Rudolph, 2010, Feedback between p21 and reactive oxygen production is necessary for cell senescence, Mol Syst Biol, 6, 347, 10.1038/msb.2010.5

González-Barroso, 2008, Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels, J Endocrinol, 19, 33

Myers, 2011, TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence, Clin Cancer Res