Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase

Cell Reports

Nanni Huser¹  Robert T. Abraham¹  Qin Shan²  Shoba Ragunathan²  Guixian Jin²  Jeremy Myers²  Natasha Emmanuel²  Fang Wang²  Keziban Unsal-Kacmaz²  Andreas Giannakou² 

[1] Oncology R&D Group, Pfizer Worldwide Research and Development, 10646 Science Center Drive/CB4, San Diego, CA 92121, USA;Oncology R&D Group, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, NY 10965, USA;

关键词: mTORC1;    GARFT;    GART;    purine biosynthesis;    GTP;    ATP;    Rheb;    farnesylation;    AG2037;    pemetrexed;   

DOI  :  10.1016/j.celrep.2017.05.043

来源: DOAJ

【 摘 要 】

Pharmacologic agents that interfere with nucleotide metabolism constitute an important class of anticancer agents. Recent studies have demonstrated that mTOR complex 1 (mTORC1) inhibitors suppress de novo biosynthesis of pyrimidine and purine nucleotides. Here, we demonstrate that mTORC1 itself is suppressed by drugs that reduce intracellular purine nucleotide pools. Cellular treatment with AG2037, an inhibitor of the purine biosynthetic enzyme GARFT, profoundly inhibits mTORC1 activity via a reduction in the level of GTP-bound Rheb, an obligate upstream activator of mTORC1, because of a reduction in intracellular guanine nucleotides. AG2037 treatment provokes both mTORC1 inhibition and robust tumor growth suppression in mice bearing non-small-cell lung cancer (NSCLC) xenografts. These results indicate that alterations in purine nucleotide availability affect mTORC1 activity and suggest that inhibition of mTORC1 contributes to the therapeutic effects of purine biosynthesis inhibitors.

【 授权许可】

Unknown