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

Abstract

The transcription factor STAT1 displays antitumor functions for certain forms of cancer via immunoregulatory and cellautonomous pathways. Paradoxically, STAT1 can promote the survival of different tumor types treated with chemotherapeutic drugs through mechanisms that are not clearly defined. Herein, we demonstrate that STAT1 displays prosurvival effects in human KRAS colon tumor cells by regulating pathways that converge on the initiation of mRNA translation. Specifically, STAT1 increases PI3K class IB signaling and promotes the downregulation of the programmed cell death protein 4 (PDCD4), a protein with tumor-suppressive properties. PDCD4 downregulation by STAT1 increases the activity of the translation initiation factor eIF4A, which facilitates the capindependent translation of mRNAs encoding for the antiapoptotic XIAP and BCL-XL in colon tumors with mutated but not normal KRAS. Genetic inactivation of STAT1 impairs the tumorigenic potency of human KRAS colon tumor cells and renders them resistant to the antitumor effects of the pharmacologic inhibition of eIF4A in culture and immunodeficient mice. Our data demonstrate an important connection between mRNA translation and KRAS tumorigenesis under the control of STAT1, which can determine the susceptibility of KRAS tumors to pharmacologic inhibition of mRNA translation initiation. Mol Cancer Ther; 15(12); 3055-63. Ó2016 AACR.

Mediator Kinase Phosphorylation of STAT1 S727 Promotes Growth of Neoplasms With JAK-STAT Activation

“…These findings are consistent with other reports of serine phosphorylation of STATs as an oncogenic post-translational modification present in many patients with hematological malignancies, among other cancers. For example, expression of phospho-deficient mutant STAT1 S727A ablates the growth of Wilms tumors as well as KRas-induced colon tumors in mice, two contexts in which STAT1 S727 is constitutively phosphorylated ( Wang et al, 2016 , Wang et al, 2008 , Timofeeva et al, 2006 ). In T-ALL, cells with TYK2 mutations or activated IL-10 signaling (which increase phosphorylated STAT1) have been shown to be dependent on a TYK2-STAT1 pathway ( Vahedi et al, 2012 , Sanda et al, 2013 , Vahedi et al, 2015 ).…”

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