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Molecular Pharmacology

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Research ArticleArticle

AKT Is Activated in an Ataxia-Telangiectasia and Rad3-Related-Dependent Manner in Response to Temozolomide and Confers Protection against Drug-Induced Cell Growth Inhibition

Simona Caporali, Lauretta Levati, Giuseppe Starace, Gianluca Ragone, Enzo Bonmassar, Ester Alvino and Stefania D'Atri
Molecular Pharmacology July 2008, 74 (1) 173-183; DOI: https://doi.org/10.1124/mol.107.044743
Simona Caporali
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Lauretta Levati
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Giuseppe Starace
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Gianluca Ragone
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Enzo Bonmassar
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Ester Alvino
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Stefania D'Atri
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Abstract

The phosphatidylinositol 3-kinase/AKT pathway is activated frequently in human cancer, and it has been implicated in tumor cell proliferation, survival, and chemoresistance. In this study, we addressed the role of AKT in cellular responses to the therapeutic methylating agent temozolomide (TMZ), and we investigated the possible link between TMZ-induced modulation of AKT function and activation of ataxia-telangiectasia and Rad3-related (ATR)- and ataxia telangiectasia mutated (ATM)-dependent signaling pathways. We found that clinically relevant concentrations of TMZ caused activation of endogenous AKT in lymphoblastoid cells, and in colon and breast cancer cells, and that this molecular event required a functional mismatch repair system. Transfection of a dominant-negative kinase-dead form of AKT1 into breast cancer cells abrogated TMZ-induced activation of endogenous AKT, and it markedly enhanced cell sensitivity to the drug. Likewise, exposure of the MMR-proficient cell lines to the AKT inhibitor d-3-deoxy-2-O-methyl-myo inositol 1-[(R)-2-methoxy-3-(octadecyloxy)-propyl hydrogen phosphate] (SH-5) impaired AKT phosphorylation in response to TMZ, and it significantly increased cell chemosensitivity. Furthermore, small interfering RNA (siRNA)-mediated reduction of AKT1 expression in colon cancer cells potentiated the growth inhibitory effects of TMZ. Inhibition of ATM expression in colon cancer cells by siRNA did not impair TMZ-induced activation of AKT, whereas siRNA-mediated inhibition of ATR prevented AKT activation in response to the drug and increased cell chemosensitivity. These results strongly support the hypothesis that clinical benefit could be obtained by combining TMZ with inhibitors of the AKT pathway. Moreover, they provide the first evidence of a novel function of ATR as an upstream activator of AKT in response to DNA damage induced by O6-guanine-methylating agents.

Footnotes

  • This study was supported by the Italian Ministry of Health.

  • ABBREVIATIONS: PI3K, phosphatidylinositol 3-kinase; PDK, 3-phosphoinositide-dependent protein kinase; IKK, IκB kinase; GSK, glycogen synthase kinase; TMZ, 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide); O6-G, O6-guanine; MGMT, O6-methylguanine-DNA methyltransferase; BG, O6-benzylguanine; MMR, mismatch repair; ATR, ataxia-telangiectasia and Rad3-related; ATM, ataxia telangiectasia mutated; SH-5, d-3-deoxy-2-O-methyl-myo inositol 1-[(R)-2-methoxy-3-(octadecyloxy) propyl hydrogen phosphate]; PBS, phosphate-buffered saline; ECL, enhanced chemiluminescence; SA-β-gal, senescence-associated β-galactosidase; siRNA, small interfering RNA; siATR, small-interfering RNA directed against ATR; siCONTROL, nonsilencing control small-interfering RNA; siATM, small-interfering RNA directed against ATM; siAKT1, small-interfering RNA directed against AKT1; scrATM, scramble small-interfering RNA negative control for ATM; scrAKT1, scramble small-interfering RNA negative control for AKT1; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; DSB, double-strand break; mAb, monoclonal antibody; p-, phospho-.

    • Received December 31, 2007.
    • Accepted April 14, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (1)
Molecular Pharmacology
Vol. 74, Issue 1
1 Jul 2008
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Research ArticleArticle

AKT Is Activated in an Ataxia-Telangiectasia and Rad3-Related-Dependent Manner in Response to Temozolomide and Confers Protection against Drug-Induced Cell Growth Inhibition

Simona Caporali, Lauretta Levati, Giuseppe Starace, Gianluca Ragone, Enzo Bonmassar, Ester Alvino and Stefania D'Atri
Molecular Pharmacology July 1, 2008, 74 (1) 173-183; DOI: https://doi.org/10.1124/mol.107.044743

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Research ArticleArticle

AKT Is Activated in an Ataxia-Telangiectasia and Rad3-Related-Dependent Manner in Response to Temozolomide and Confers Protection against Drug-Induced Cell Growth Inhibition

Simona Caporali, Lauretta Levati, Giuseppe Starace, Gianluca Ragone, Enzo Bonmassar, Ester Alvino and Stefania D'Atri
Molecular Pharmacology July 1, 2008, 74 (1) 173-183; DOI: https://doi.org/10.1124/mol.107.044743
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