Activation of the PIK3CA/AKT Pathway Suppresses Senescence Induced by an Activated RAS Oncogene to Promote Tumorigenesis

Molecular Cell

Volumn 42, Issue 1, 2011, Pages 36-49

  Kennedy, Alyssa L ^c,d   Morton, Jennifer P ^b   Manoharan, Indrani ^a   Nelson, David M ^a   Jamieson, Nigel B ^a,e   Pawlikowski, Jeff S ^a   McBryan, Tony ^a   Doyle, Brendan ^b   McKay, Colin ^e   Oien, Karin A ^a   Enders, Greg H ^d   Zhang, Rugang ^d   Sansom, Owen J ^b   Adams, Peter D ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

^b BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

^c DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

^d FOX CHASE CANCER CENTER   (United States)

^e GLASGOW ROYAL INFIRMARY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; RAS PROTEIN;

AKT GENE; ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CANCER THERAPY; CARCINOGENESIS; CONTROLLED STUDY; GENE ACTIVATION; GENE MUTATION; HUMAN; HUMAN CELL; HUMAN TISSUE; MOUSE; NONHUMAN; ONCOGENE; ONCOGENE RAS; PANCREAS CANCER; PIK3CA GENE; SENESCENCE; TUMOR GROWTH;

AGED; ANIMALS; CELL AGING; CELL LINE, TRANSFORMED; CELL PROLIFERATION; DISEASE MODELS, ANIMAL; ENZYME ACTIVATION; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; GENES, RAS; HUMANS; MALE; MICE; MICE, KNOCKOUT; MICE, TRANSGENIC; MIDDLE AGED; MUTATION; NEOPLASMS; PANCREATIC NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; PTEN PHOSPHOHYDROLASE; SIGNAL TRANSDUCTION;

EID: 79953315567     PISSN: 10972765     EISSN: 10974164     Source Type: Journal    
DOI: 10.1016/j.molcel.2011.02.020     Document Type: Article

References (60)

1. Acosta J.C., O'Loghlen A., Banito A., Guijarro M.V., Augert A., Raguz S., Fumagalli M., Da Costa M., Brown C., Popov N., et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 2008, 133:1006-1018.
2. Adams P.D. Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol. Cell 2009, 36:2-14.
3. Alimonti A., Nardella C., Chen Z., Clohessy J.G., Carracedo A., Trotman L.C., Cheng K., Varmeh S., Kozma S.C., Thomas G., et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J. Clin. Invest. 2010, 120:681-693.
4. Altomare D.A., Tanno S., De Rienzo A., Klein-Szanto A.J., Skele K.L., Hoffman J.P., Testa J.R. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J. Cell. Biochem. 2002, 87:470-476.
5. Asano T., Yao Y., Zhu J., Li D., Abbruzzese J.L., Reddy S.A. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells. Oncogene 2004, 23:8571-8580.
6. Banumathy G., Somaiah N., Zhang R., Tang Y., Hoffmann J., Andrake M., Ceulemans H., Schultz D., Marmorstein R., Adams P.D. Human UBN1 is an ortholog of yeast Hpc2p and has an essential role in the HIRA/ASF1a chromatin-remodeling pathway in senescent cells. Mol. Cell. Biol. 2009, 29:758-770.
7. Braig M., Lee S., Loddenkemper C., Rudolph C., Peters A.H., Schlegelberger B., Stein H., Dorken B., Jenuwein T., Schmitt C.A. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 2005, 436:660-665.
8. Brose M.S., Volpe P., Feldman M., Kumar M., Rishi I., Gerrero R., Einhorn E., Herlyn M., Minna J., Nicholson A., et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002, 62:6997-7000.
9. Chen Z., Trotman L.C., Shaffer D., Lin H.K., Dotan Z.A., Niki M., Koutcher J.A., Scher H.I., Ludwig T., Gerald W., et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005, 436:725-730.
10. Collado M., Gil J., Efeyan A., Guerra C., Schuhmacher A.J., Barradas M., Benguria A., Zaballos A., Flores J.M., Barbacid M., et al. Tumour biology: senescence in premalignant tumours. Nature 2005, 436:642.
11. Coppe J.P., Patil C.K., Rodier F., Sun Y., Munoz D.P., Goldstein J., Nelson P.S., Desprez P.Y., Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008, 6:2853-2868.
12. Courtois-Cox S., Genther Williams S.M., Reczek E.E., Johnson B.W., McGillicuddy L.T., Johannessen C.M., Hollstein P.E., MacCollin M., Cichowski K. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 2006, 10:459-472.
13. Cross D.A., Alessi D.R., Cohen P., Andjelkovich M., Hemmings B.A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995, 378:785-789.
14. d'Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 2008, 8:512-522.
15. Dankort D., Filenova E., Collado M., Serrano M., Jones K., McMahon M. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 2007, 21:379-384.
16. Davies H., Bignell G.R., Cox C., Stephens P., Edkins S., Clegg S., Teague J., Woffendin H., Garnett M.J., Bottomley W., et al. Mutations of the BRAF gene in human cancer. Nature 2002, 417:949-954.
17. Deng C., Zhang P., Harper J.W., Elledge S.J., Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 1995, 82:675-684.
18. Dimri G.P., Lee X., Basile G., Acosta M., Scott G., Roskelley C., Medrano E.E., Linskens M., Rubelj I., Pereira-Smith O., et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA 1995, 92:9363-9367.
19. Ebert M.P., Fei G., Schandl L., Mawrin C., Dietzmann K., Herrera P., Friess H., Gress T.M., Malfertheiner P. Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1. Br. J. Cancer 2002, 86:257-262.
20. Gamerdinger M., Hajieva P., Kaya A.M., Wolfrum U., Hartl F.U., Behl C. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. EMBO J. 2009, 28:889-901.
21. Ha L., Ichikawa T., Anver M., Dickins R., Lowe S., Sharpless N.E., Krimpenfort P., Depinho R.A., Bennett D.C., Sviderskaya E.V., et al. ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence. Proc. Natl. Acad. Sci. USA 2007, 104:10968-10973.
22. He C., Klionsky D.J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 2009, 43:67-93.
23. Hill R., Calvopina J.H., Kim C., Wang Y., Dawson D.W., Donahue T.R., Dry S., Wu H. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res. 2010, 70:7114-7124.
24. Hingorani S.R., Petricoin E.F., Maitra A., Rajapakse V., King C., Jacobetz M.A., Ross S., Conrads T.P., Veenstra T.D., Hitt B.A., et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003, 4:437-450.
25. Holland E.C., Celestino J., Dai C., Schaefer L., Sawaya R.E., Fuller G.N. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat. Genet. 2000, 25:55-57.
26. Kim T.H., Wang J., Lee K.Y., Franco H.L., Broaddus R.R., Lydon J.P., Jeong J.W., Demayo F.J. The synergistic effect of conditional Pten loss and oncogenic K-ras mutation on endometrial cancer development occurs via decreased progesterone receptor action. J. Oncol. 2010, 2010:139087. Published online October 27, 2009. 10.1155/2010/139087.
27. Klionsky D.J., Abeliovich H., Agostinis P., Agrawal D.K., Aliev G., Askew D.S., Baba M., Baehrecke E.H., Bahr B.A., Ballabio A., et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008, 4:151-175.
28. Kortlever R.M., Higgins P.J., Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat. Cell Biol. 2006, 8:877-884.
29. Kuilman T., Michaloglou C., Vredeveld L.C., Douma S., van Doorn R., Desmet C.J., Aarden L.A., Mooi W.J., Peeper D.S. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008, 133:1019-1031.
30. Lin A.W., Barradas M., Stone J.C., van Aelst L., Serrano M., Lowe S.W. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998, 12:3008-3019.
31. Liu S., Fang X., Hall H., Yu S., Smith D., Lu Z., Fang D., Liu J., Stephens L.C., Woodgett J.R., et al. Homozygous deletion of glycogen synthase kinase 3beta bypasses senescence allowing Ras transformation of primary murine fibroblasts. Proc. Natl. Acad. Sci. USA 2008, 105:5248-5253.
32. Majumder P.K., Grisanzio C., O'Connell F., Barry M., Brito J.M., Xu Q., Guney I., Berger R., Herman P., Bikoff R., et al. A prostatic intraepithelial neoplasia-dependent p27 Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression. Cancer Cell 2008, 14:146-155.
33. Michaloglou C., Vredeveld L.C., Soengas M.S., Denoyelle C., Kuilman T., van der Horst C.M., Majoor D.M., Shay J.W., Mooi W.J., Peeper D.S. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 2005, 436:720-724.
34. Miller K.A., Yeager N., Baker K., Liao X.H., Refetoff S., Di Cristofano A. Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo. Cancer Res. 2009, 69:3689-3694.
35. Miyauchi H., Minamino T., Tateno K., Kunieda T., Toko H., Komuro I. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J. 2004, 23:212-220.
36. Morton J.P., Jamieson N.B., Karim S.A., Athineos D., Ridgway R.A., Nixon C., McKay C.J., Carter R., Brunton V.G., Frame M.C., et al. LKB1 haploinsufficiency cooperates with Kras to promote pancreatic cancer through suppression of p21-dependent growth arrest. Gastroenterology 2010, 139:586-597. 597 e581-e586.
37. Morton J.P., Timpson P., Karim S.A., Ridgway R.A., Athineos D., Doyle B., Jamieson N.B., Oien K.A., Lowy A.M., Brunton V.G., et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2010, 107:246-251.
38. Narita M., Nunez S., Heard E., Lin A.W., Hearn S.A., Spector D.L., Hannon G.J., Lowe S.W. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003, 113:703-716.
39. Nogueira V., Park Y., Chen C.C., Xu P.Z., Chen M.L., Tonic I., Unterman T., Hay N. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 2008, 14:458-470.
40. Okami K., Wu L., Riggins G., Cairns P., Goggins M., Evron E., Halachmi N., Ahrendt S.A., Reed A.L., Hilgers W., et al. Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumors. Cancer Res. 1998, 58:509-511.
41. Oyama K., Okawa T., Nakagawa H., Takaoka M., Andl C.D., Kim S.H., Klein-Szanto A., Diehl J.A., Herlyn M., El-Deiry W., et al. AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture. Oncogene 2007, 26:2353-2364.
42. Parsons D.W., Wang T.L., Samuels Y., Bardelli A., Cummins J.M., DeLong L., Silliman N., Ptak J., Szabo S., Willson J.K., et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005, 436:792.
43. Pollock P.M., Meltzer P.S. A genome-based strategy uncovers frequent BRAF mutations in melanoma. Cancer Cell 2002, 2:5-7.
44. Ruggeri B.A., Huang L., Wood M., Cheng J.Q., Testa J.R. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog. 1998, 21:81-86.
45. Sarkisian C.J., Keister B.A., Stairs D.B., Boxer R.B., Moody S.E., Chodosh L.A. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat. Cell Biol. 2007, 9:493-505.
46. Schlieman M.G., Fahy B.N., Ramsamooj R., Beckett L., Bold R.J. Incidence, mechanism and prognostic value of activated AKT in pancreas cancer. Br. J. Cancer 2003, 89:2110-2115.
47. Semba S., Moriya T., Kimura W., Yamakawa M. Phosphorylated Akt/PKB controls cell growth and apoptosis in intraductal papillary-mucinous tumor and invasive ductal adenocarcinoma of the pancreas. Pancreas 2003, 26:250-257.
48. Shaw R.J., Cantley L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006, 441:424-430.
49. Stanger B.Z., Stiles B., Lauwers G.Y., Bardeesy N., Mendoza M., Wang Y., Greenwood A., Cheng K.H., McLaughlin M., Brown D., et al. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 2005, 8:185-195.
50. Sun P., Yoshizuka N., New L., Moser B.A., Li Y., Liao R., Xie C., Chen J., Deng Q., Yamout M., et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell 2007, 128:295-308.
51. Suzuki A., Yamaguchi M.T., Ohteki T., Sasaki T., Kaisho T., Kimura Y., Yoshida R., Wakeham A., Higuchi T., Fukumoto M., et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 2001, 14:523-534.
52. Tresini M., Mawal-Dewan M., Cristofalo V.J., Sell C. A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblasts. Cancer Res. 1998, 58:1-4.
53. Tuveson D.A., Hingorani S.R. Ductal pancreatic cancer in humans and mice. Cold Spring Harb. Symp. Quant. Biol. 2005, 70:65-72.
54. Ventura A., Kirsch D.G., McLaughlin M.E., Tuveson D.A., Grimm J., Lintault L., Newman J., Reczek E.E., Weissleder R., Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature 2007, 445:661-665.
55. Xue W., Zender L., Miething C., Dickins R.A., Hernando E., Krizhanovsky V., Cordon-Cardo C., Lowe S.W. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 2007, 445:656-660.
56. Ye X., Zerlanko B., Kennedy A., Banumathy G., Zhang R., Adams P.D. Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol. Cell 2007, 27:183-196.
57. Yeang C.H., McCormick F., Levine A. Combinatorial patterns of somatic gene mutations in cancer. FASEB J. 2008, 22:2605-2622.
58. Young A.R., Narita M., Ferreira M., Kirschner K., Sadaie M., Darot J.F., Tavare S., Arakawa S., Shimizu S., Watt F.M. Autophagy mediates the mitotic senescence transition. Genes Dev. 2009, 23:798-803.
59. Zhang R., Poustovoitov M.V., Ye X., Santos H.A., Chen W., Daganzo S.M., Erzberger J.P., Serebriiskii I.G., Canutescu A.A., Dunbrack R.L., et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 2005, 8:19-30.
60. Zmijewski J.W., Jope R.S. Nuclear accumulation of glycogen synthase kinase-3 during replicative senescence of human fibroblasts. Aging Cell 2004, 3:309-317.