Defining the Role of PIM in Regulating Cytoskeletal Dynamics and Tumor Cell Invasion in Hypoxia

Abstract

Invasion of tumor cells out of the primary site is an essential early step in metastasis, which is responsible for the majority of cancer deaths. Therefore, distinguishing key factors that drive the switch from indolent to invasive disease will make a significant impact on guiding the treatment of prostate cancer (PCa) patients. Here, we identify a novel signaling pathway that links hypoxia and Proviral Integration site for Moloney murine leukemia virus (PIM) 1 kinase to the actin cytoskeleton and cell motility. PIM1 is upregulated in hypoxia and known to promote tumor survival and growth, but its role in invasion and metastasis has not been established. An unbiased proteomic screen identified Abl-interactor 2 (ABI2), an integral member of the Wave Regulatory Complex (WRC) that controls cytoskeletal dynamics, as a novel PIM1 substrate. Biochemical studies demonstrated that phosphorylation of ABI2 at Ser183 by PIM1 increased ABI2 protein levels, which enhanced WRC-mediated activation of actin-related protein (ARP) 2/3, resulting in increased protrusive activity and cell motility. Knockout of ABI2 diminished protrusive activity and negated the sufficiency of hypoxia and/or PIM1 to induce cellular protrusion. In vivo (skeletal) muscle invasion assays showed that overexpression of PIM1 significantly increased the depth of tumor cell invasion in an ABI2-dependent manner, and treatment with a clinically available PIM inhibitor significantly reduced intramuscular PCa invasion. This research uncovers a HIF-1-independent signaling axis that is critical for hypoxia-induced invasion and establishes a novel role for PIM1 as a key regulator of the actin cytoskeleton.