Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-04, Vol.112 (17), p.E2149-E2155
• Main Authors: Wang, Shuo, Patsis, Christos, Koromilas, Antonis E.
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; antineoplastic agents; Apoptosis; Biological Sciences; cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells; Class Ib Phosphatidylinositol 3-Kinase; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Doxorubicin - pharmacology; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - metabolism; immune response; messenger RNA; Mice; Mice, Knockout; neoplasms; Peptide Chain Initiation, Translational - drug effects; Peptide Chain Initiation, Translational - physiology; phosphatidylinositol 3-kinase; PNAS Plus; protein synthesis; Proteins; Ribonucleic acid; RNA; RNA Caps - genetics; RNA Caps - metabolism; Signal transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; translation (genetics); Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1420671112

The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27 ᴷⁱᵖ¹ and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs. Significance Stat1 functions as a tumor suppressor by inhibiting cell proliferation and mediating antitumor immune responses. Thus, Stat1 is thought to be a suitable target for the implementation of effective antitumor therapies. However, recent findings have shown that Stat1 can mediate resistance to antitumor drugs through mechanisms that are not well understood. Herein, we demonstrate the ability of Stat1 to induce phosphoinositide 3-kinase γ (PI3Kγ) signaling and inhibit general protein synthesis, which results in the translation of select mRNAs encoding for proteins that inhibit cell proliferation or render cells increasingly resistant to antitumor drugs. Our work may result in the design of therapies that disarm the prosurvival function of Stat1 in tumors without compromising its ability to mount an effective antitumor immune response.