AMP-activated Protein Kinase (AMPK) Control of mTORC1 Is p53- and TSC2-independent in Pemetrexed-treated Carcinoma Cells

Journal of Biological Chemistry

Volumn 290, Issue 46, 2015, Pages 27476-27486

  Agarwal, Stuti ^a   Bell, Catherine M ^a   Rothbart, Scott B ^b   Moran, Richard G ^a  

^a VIRGINIA COMMONWEALTH UNIVERSITY   (United States)

^b VAN ANDEL RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOSYNTHESIS; CHEMICAL ACTIVATION; MAMMALS; PHOSPHORYLATION; TRANSCRIPTION;

AMP-ACTIVATED PROTEIN KINASE; CARCINOMA CELLS; ENERGY STATUS; MAMMALIAN CELLS; MONOPHOSPHATES; P53 FUNCTION; RIBONUCLEOSIDES; TRANSCRIPTIONAL RESPONSE;

ENZYME ACTIVITY;

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PEMETREXED; PROTEIN P53; RAPTOR PROTEIN; TUBERIN; UNCLASSIFIED DRUG; 5 AMINO 4 IMIDAZOLECARBOXAMIDE; AICA RIBONUCLEOTIDE; ANTINEOPLASTIC AGENT; CHECKPOINT KINASE 2; CHEK2 PROTEIN, HUMAN; FOLIC ACID ANTAGONIST; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEX; RIBONUCLEOTIDE; RPTOR PROTEIN, HUMAN; SIGNAL TRANSDUCING ADAPTOR PROTEIN; TARGET OF RAPAMYCIN KINASE; TUMOR SUPPRESSOR PROTEIN;

ARTICLE; CARCINOMA CELL; CONTROLLED STUDY; DRUG EFFECT; ENZYME ACTIVATION; GENE TARGETING; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN STABILITY; PROTEIN SUBUNIT; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR GENE; ANALOGS AND DERIVATIVES; DRUG EFFECTS; GENETICS; HCT 116 CELL LINE; METABOLISM; PHOSPHORYLATION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; AMINOIMIDAZOLE CARBOXAMIDE; AMP-ACTIVATED PROTEIN KINASES; ANTINEOPLASTIC AGENTS; CHECKPOINT KINASE 2; ENZYME ACTIVATION; FOLIC ACID ANTAGONISTS; HCT116 CELLS; HUMANS; MULTIPROTEIN COMPLEXES; PEMETREXED; PHOSPHORYLATION; RIBONUCLEOTIDES; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; TRANSCRIPTION, GENETIC; TUMOR SUPPRESSOR PROTEIN P53; TUMOR SUPPRESSOR PROTEINS;

EID: 84946899816     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.665133     Document Type: Article

References (65)

1. Shaw, R.J., and Cantley, L. (2006) Ras, PI(3)K and mTOR signaling controls tumour cell growth. Nature 441, 424-430
2. Aoki M., Blazek, E., and Vogt, P.K. (2001) A role of the kinase mTOR in cellular transformation induced by the oncoproteins PI3k and Akt. Proc. Natl. Acad. Sci. U.S.A. 98, 136-141
3. Vivanco, I., and Sawyers, C.L. (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2, 489-501
4. Sansal, I., and Sellers, W.R. (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J. Clin. Oncol. 22, 2954-2963
5. Schalm, S.S., Fingar, D.C., Sabatini, D.M., Blenis, J. (2003) TOS motif-mediated Raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 13, 797-806
6. Hara, K., Maruki, Y., Long, X., Yoshino, K., Oshiro, N., Hidayat, S., Tokunaga, C., Avruch, J., and Yonezawa, K. (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177-189
7. Nojima, H., Tokunaga, C., Eguchi, S., Oshiro, N., Hidayat, S., Yoshino, K., Hara, K., Tanaka, N., Avruch, J., and Yonezawa, K. (2003) The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J. Biol. Chem. 278, 15461-15464
8. Courtney, K. D., and Corcoran, R. B., and Engelman, J. A. (2010) The PI3K pathway as a drug target in human cancer. J. Clin. Oncol. 28, 1075-1083
9. Workman, P., and Clarke, P. A., Raynaud, F. I., and van Montfort R. L. (2010) Drugging the PI3 kinome: from chemical tools to drugs in the clinic. CancerRes. 70, 2146-2157
10. Hsieh, A. C., Costa, M., Zollo, O., Davis, C., Feldman, M. E., Testa, J. R., Meyuhas, O., Shokat, K. M., and Ruggero, D. (2010) Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell 17, 249-261
11. Courtois-Cox, S., Genther Williams, S. M., Reczek, E. E., Johnson, B. W., McGillicuddy, L. T., Johannessen, C. M., Hollstein, P. E., MacCollin, M., and Cichowski, K. (2006) A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell 10, 459-472
12. O'Reilly, K. E., Rojo, F., She, Q. B, Solit, D., Mills, G.B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., Baselga, J., and Rosen, N. (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500-1508
13. Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., and Sasaki, A. T., Thomas, G., Kozma, S. C., Papa, A., Nardella, C., Cantley, L. C., Baselga, J., and Pandolfi, P. P. (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J. Clin. Invest. 118, 3065-3074
14. Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., and Majumder, P. K., Baselga, J., and Rosen, N. (2011) PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Cancer Cell 19, 58-71
15. Huang, J., and Manning, B.D. (2008) The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem. J. 412, 179-190
16. Sancak, Y., Thoreen, C. C., Peterson, T. R., Lindquist, R. A., Kang, S. A., Spooner, E., Carr, S. A., and Sabatini, D. M. (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903-915
17. Inoki, K., Li, Y., Zhu, T., Wu, J., and Guan, K. L. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat. Cell Biol. 4, 648-657
18. Manning, B. D., and Tee, A. R., Logsdon, M. N., Blenis, J., and Cantley, L. C. (2002) Identification of the tuberous sclerosis complex-2 tumour suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol. Cell 10, 151-162
19. Inoki, K., Li, Y., Xu, T., and Guan, K. L. (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829-1834
20. Kwiatkowski, D.J., and Manning B.D. (2005) Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum. Mol. Genet. 15, R251-R258
21. Mihaylova, M. M., and Shaw, R. J. (2011) The AMPK signaling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016-1023
22. Hardie, D. G., and Ross, F. A., and Hawley, S. A. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251-262
23. Hawley, S. A., Davison, M., Woods, A., Davies, S. P., and Beri, R. K., Carling, D., and Hardie, D. G. (1996) Characterization of the AMP-activated protein kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271, 27879-27887
24. Hardie, D. G., Carling, D., and Carlson, M. (1998) The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu. Rev. Biochem. 67, 821-855
25. Inoki, K., Zhu, T., and Guan, K. L. (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590
26. Gwinn, D. M., and Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., and Vasquez, D. S., Turk, B. E., and Shaw, R. J. (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214-226
27. Budanov, A.V., and Karin, M. (2008) p53 target genes Sestrin1 and Sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451-460
28. Sancak, Y., Bar-Peled, L., Zoncu, R., and Markhard, A. L., Nada, S., and Sabatini, D. M. (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290-303
29. Menon, S., Dibble, C. C., Talbott, G., Hoxhaj, G., Valvezan, A. J., Takahashi, H., Cantley, L. C., and Manning, B. D. (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156, 771-785
30. Chantranupong, L., and Wolfson, R. L., Orozco, J. M., Saxton, RA., Scaria, S. M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S. P., and Sabatini, D. M. (2014) The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9, 1-8
31. Feng, Z., Hu, W., de Stanchina, E., Teresky, A. K., Jin, S., Lowe, S., and Levine, A. J. (2007) The regulation of AMPKβ1, 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. Cancer Res. 67, 3043-3053
32. Agarwal, S., Bell, C., and Taylor, S. M., and Moran, R. G. (2015) Deletion or hot-spot mutations of p53 enhance mTORC1 activity by changing the lysosomal partitioning of TSC2 and Rheb. Mol. Cancer Res. pii: molcanres.0159.2015
33. Ding, L., Getz, G., Wheeler, D. A., and Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., and Muzny, D. M., Morgan, M. B., Fulton, L., Fulton, R. S., Zhang, Q., Wendl, M. C., Lawrence, M. S., Larson, D. E., Chen, K., Dooling, D. J., Sabo, A., Hawes, A. C., Shen, H., Jhangiani, S. N., Lewis, L. R., Hall, O., Zhu, Y., Mathew, T., Ren, Y., Yao, J., Scherer, S. E., Clerc, K., Metcalf, G. A., Ng, B., Milosavljevic, A., Gonzalez-Garay, M. L., Osborne, J. R., Meyer, R., Shi, X., Tang, Y., Koboldt, D. C., Lin, L., Abbott, R., Miner, T. L., Pohl, C., Fewell, G., Haipek, C., Schmidt, H., Dunford-Shore, B. H., Kraja, A., Crosby, S. D., Sawyer, C. S., Vickery, T., et al. (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069-1075
34. Woods, A., and Johnstone, S. R., Dickerson, K., Leiper, F. C., Fryer, L. G., Neumann, D., Schlattner, U., Wallimann, T., Carlson, M., and Carling, D. (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004-2008
35. Sanchez-Cespedes, M., Parrella, P., Esteller, M., Nomoto, S., Trink, B., and Engles, J. M., Westra, W. H., Herman, J. G., and Sidransky, D. (2002) Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62, 3659-3662
36. Corton, J. M., and Gillespie, J. G., Hawley, S. A., and Hardie, D. G. (1995) 5-Aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells. Eur. J. Biochem. 229, 558-565
37. Hawley, S. A., and Ross, F. A., Chevtzoff, C., and Green, K. A., Evans, A., Fogarty, S., Towler, M. C., Brown, L. J., Ogunbayo, O. A., Evans, A. M., and Hardie, D. G. (2010) Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. CellMetab. 11, 554-565
38. Racanelli, A. C., Rothbart, S. B., Heyer, C. L., and Moran, R. G. (2009) Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res. 69, 5467-5474
39. Rothbart, S. B., Racanelli, A. C., and Moran, R. G. (2010) Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas. Cancer Res. 70, 10299-10309
40. Taylor, E. C., Kuhnt, D., Shih, C., Rinzel, S. M., Grindey, G. B., Barredo, J., Jannatipour, M., and Moran, R. G. (1992) A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3, 4-dihydro-4-oxo-7H-pyrrolo[2, 3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid is an inhibitor of thymidylate synthase. J. Med. Chem. 35, 4450-4454
41. Shih, C., and Chen, V. J., Gossett, L. S., Gates, S. B., MacKellar, W. C., Habeck, L. L., Shackelford, K. A., Mendelsohn, L. G., Soose, D. J., Patel, V. F., Andis, S. L., Bewley, J. R., Rayl, E. A., Moroson, B. A., Beardsley, G. P., Kohler, W., Ratnam, M., and Schultz, R.M. (1997) LY231514, apyrrolo[2, 3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res. 57, 1116-1123
42. Sengupta, T. K., and Leclerc, G. M., Hsieh-Kinser, T. T., Leclerc, G. J., Singh, I., and Barredo, J. C. (2007) Cytotoxic effect of 5-aminoimidaz-ole-4-carboxamide-1-β-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: implication for targeted therapy. Mol. Cancer 6, 46-60
43. Rattan, R., Giri, S., Singh, A. K., and Singh, I. (2005) 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside inhibits cancer cell proliferation in vitro and In vivo via AMP-activated protein kinase. J. Biol. Chem. 280, 39582-39593
44. Riley, T., Sontag, E., Chen, P., and Levine, A. (2008) Transcriptional control of human p53-regulated genes. Nat. Rev. Mol. Cell Biol. 9, 402-412
45. Siliciano, J. D., and Canman, C. E., Taya, Y., Sakaguchi, K., Appella, E., and Kastan, M. B. (1997) DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 11, 3471-3481
46. Appella, E., and Anderson, C. W. (2001) Post-translational modifications and activation of p53 by genotoxic stresses. Eur. J. Biochem. 268, 2764-2772
47. Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y., and Prives, C. (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14, 289-300
48. Vecchio, D., Daga, A., Carra, E., Marubbi, D., Baio, G., Neumaier, C. E., Vagge, S., Corvò, R., Pia Brisigotti, M., Louis Ravetti, J., Zunino, A., Poggi, A., Mascelli, S., Raso, A., and Frosina, G. (2014) Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019. Int. J. Cancer 135, 479-491
49. Jones, R. G., and Plas, D. R., Kubek, S., Buzzai, M., Mu, J., Xu, Y., Birnbaum, M. J., and Thompson, C. B. (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283-293
50. Weeks, L.D., Zentner, G. E., and Scacheri, P. C., and Gerson, S. L. (2014) Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed. Cell Death Dis. 5, e1045
51. Rothbart, S. B. (2010) Antifolate Modulators of AMP-activated Protein Kinase Signaling as Cancer Therapeutics. Doctoral dissertation, Virginia Commonwealth University, Richmond, VA
52. Holz, M. K., and Ballif, B. A., Gygi, S. P., and Blenis, J. (2005) mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569-580
53. Gingras, A. C., Raught, B., and Sonenberg, N. (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev. 15, 807-826
54. Peng, M., Yin, N., and Li, M. O. (2014) Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159, 122-133
55. Jobson A. G., Lountos, G. T., and Lorenzi, P. L., Llamas, J., Connelly, J., Cerna, D., and Tropea, J. E., Onda, A., Zoppoli, G., Kondapaka, S., Zhang, G., Caplen, N. J., and Cardellina, J. H., 2nd, Yoo, S. S., Monks, A., Self, C., Waugh, D. S., Shoemaker, R. H., and Pommier, Y. (2009) Cellular inhibition of checkpoint kinase 2 (Chk2) and potentiation of camptothecins and radiation by the novel Chk2 inhibitor PV1019 [7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide]. J. Pharmacol. Exp. Ther. 331, 816-826
56. Leung-Pineda, V., Ryan, C. E., and Piwnica-Worms, H. (2006) Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit. Mol. Cell. Biol. 26, 7529-7538
57. Beckerman, R., and Donner, A. J., Mattia, M., Peart, M. J., and Manley, J. L., Espinosa, J. M., and Prives, C. (2009) A role for Chk1 in blocking transcriptional elongation of p21 RNA during the S-phase checkpoint. Genes Dev. 23, 1364-1377
58. Moran, R. G., and Baldwin, S. W., Taylor, E.C., and Shih, C. (1989) The 6S- and 6R-diastereomers of 5, 10-dideaza-5, 6, 7, 8-tetrahydrofolate are equiactive inhibitors of de novo purine synthesis. J. Biol. Chem. 264, 21047-21051
59. Ward, I. M., and Chen, J. (2001) Histone H2AX is phosphorylated in an ATR-dependent manner in response to replication stress. J. Biol. Chem. 276, 47759-47762
60. Tonkinson, J.L., Marder, P., Andis, S.L., Schultz, R.M., Gossett, L.S., Shih, C., and Mendelsohn, L. G. (1997) Cell cycle effects of antifolate antimetabolites: implications for cytotoxicity and cytostasis. Cancer Chemother. Pharmacol. 39, 521-531
61. Sun, S. Y., and Rosenberg, L. M., Wang, X., Zhou, Z., Yue, P., Fu, H., and Khuri, F. R. (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 65, 7052-7058
62. Noh, W. C., Mondesire, W.H., Peng, J., Jian, W., Zhang, H., Dong, J., Mills, G. B., and Hung, M. C., and Meric-Bernstam, F. (2004) Determinants of rapamycin sensitivity in breast cancer cells. Clin. Cancer Res. 10, 1013-1023
63. Mondesire, W. H., Jian, W., Zhang, H., Ensor, J., and Hung, M. C., Mills, G. B., and Meric-Bernstam, F. (2004) Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin. Cancer Res. 10, 7031-7042
64. Bronder, J. L., and Moran, R. G. (2003) A defect in the p53 response pathway induced by de novo purine synthesis inhibition. J. Biol. Chem. 278, 48861-48871
65. Gottifredi, V., Shieh, S., Taya, Y., and Prives, C. (2001) p53 accumulates but is functionally impaired when DNA synthesis is blocked. Proc. Natl. Acad. Sci. U.S.A. 98, 1036-1041