Abstract 263: PIM kinase regulates actin dynamics in hypoxia

Abstract

Abstract One of the leading factors in prostate cancer mortality is the onset of metastatic events. This is seen by the drastic decline in survival rates following tumor escape from the primary site. A key promoter of metastasis is tumor hypoxia, or low oxygen concentration. Our lab previously demonstrated that Proviral Integration site for Moloney murine leukemia virus (PIM)-1, a serine-threonine kinase, is upregulated in hypoxia and that inhibition of PIM1 reduced metastatic occurrence in orthotopic mouse models. Here, we identify a novel signaling pathway that links hypoxia and PIM kinase to the actin cytoskeleton and cell motility. An unbiased screen to discover new PIM substrates in hypoxia identified Abl-Interactor 2 (Abi2), an integral member of the actin regulating Wave Regulatory Complex (WRC), as a novel PIM kinase substrate. Biochemical analysis demonstrates that phosphorylation of Abi2 at our identified PIM sites increases Abi2 stability. Overexpression of PIM1 increases Abi2 and other WRC members at the protein level, resulting in increased actin protrusions and cell motility. CRISPR-generated Abi2 knockout cell lines showed diminished protrusive activity and negated both the necessity and sufficiency of PIM kinase to increases protrusive activity in cancer cells. Lastly, in vivo experiments show that overexpression of PIM1 increases tumor invasion into the surrounding tissue in an Abi2-dependent manner, and small molecule PIM inhibitors significantly reduce invasion. In summary, we uncovered a novel role for PIM1 in promoting cellular motility and protrusion, identified novel phosphorylation sites that control the stability of Abi2 in normoxic and hypoxic conditions, and highlight a novel PIM1/Abi2 signaling axis that regulates hypoxia-induced tumor invasion. This research provides important insight in the role of PIM signaling in prostate tumors and yields preclinical evidence for further use of PIM kinase inhibitors as a means to inhibit tumor invasion, a key driving step in the formation of lethal prostate cancer metastasis. Citation Format: Corbin C. Jensen, Noel A. Warfel. PIM kinase regulates actin dynamics in hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 263.