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

Abstract

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 p27Kip1 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.

STAT1 Promotes KRAS Colon Tumor Growth and Susceptibility to Pharmacological Inhibition of Translation Initiation Factor eIF4A

“…Increased PI3K signaling by STAT1 was responsible for the degradation of programmed cell death protein 4 (PDCD4), which resulted in increased activity of the translation initiation factor eIF4A and efficient translation of mRNAs encoding for the prosurvival X-linked inhibitor of apoptosis (XIAP) and B-cell lymphoma xl (BCL-XL; ref. 14). We showed that the ability of STAT1 to promote XIAP and BCL-XL expression at the translational level significantly contributed to the survival of immortalized and HRAS G12V-transformed MEFs to treatments with PI3K and mTOR inhibitors or genotoxic drugs like doxorubicin (14).…”

“…14). We showed that the ability of STAT1 to promote XIAP and BCL-XL expression at the translational level significantly contributed to the survival of immortalized and HRAS G12V-transformed MEFs to treatments with PI3K and mTOR inhibitors or genotoxic drugs like doxorubicin (14).…”

“…Transfections of di-cistronic reporter gene constructs containing the XIAP or BCL-Xl 5 0 untranslated region (UTR) were described previously (14). Quantification of b-galactosidase and chloramphenicol acetyltransferase (CAT) activity was performed as described previously (21).…”

“…14). Increased PI3K signaling by STAT1 was responsible for the degradation of programmed cell death protein 4 (PDCD4), which resulted in increased activity of the translation initiation factor eIF4A and efficient translation of mRNAs encoding for the prosurvival X-linked inhibitor of apoptosis (XIAP) and B-cell lymphoma xl (BCL-XL; ref.…”

“…Considering that the translational effects of STAT1 on cell survival were characterized in MEFs transformed by HRAS G12V overexpression (14), we investigated STAT1 0 s function in human colorectal carcinoma HCT116 cells bearing an endogenous activated KRAS allele. We demonstrate that the translational and prosurvival effects of STAT1 are especially relevant for human colon tumor cells with an activated KRAS allele and not for isogenic tumors with normal KRAS.…”