PIM Kinase as an Executional Target in Cancer

Abstract

PIM (proviral integration site for moloney murine leukemia virus) kinase plays a key role as an oncogene in various cancers including myeloma, leukemia, prostate and breast cancers. The aberrant expression and/or activation of PIM kinases in various cancers follow an isoform-specific pattern. While PIM1 is predominantly expressed in hematological and solid tumors, PIM2 and PIM3 are largely expressed in leukemia and solid tumors, respectively. All of PIM kinases cause transcriptional activation of genes involved in cell survival and cell cycle progression in cancer. A variety of pro-tumorigenic signaling molecules, such as MYC, p21^Cip1/Waf1/p27^kip1, CDC25, Notch1 and BAD have been identified as the downstream targets of PIM kinases. So far, three kinds of adenosine triphosphate-competitive PIM inhibitors, SGI-1776, AZD1208, and LGH447 have been in clinical trials for the treatment of acute myelogenous leukemia, prostate cancer, lymphoma, or multiple myeloma. This review sheds light on the signaling pathways involved in the PIM kinase regulation and current status of developing PIM kinase inhibitors as clinical success in combating human cancer.

Keywords: PIM kinase inhibitor; PIM signaling pathways; Proto-oncogene proteins PIM kinase.

Figure 1

The substrates of PIM (proviral integration site for moloney murine leukemia virus) kinase. PIM activates genes transcription and cell cycles, and inhibits apoptosis of cells by directly or indirectly regulation of targets. PIM directly phophorylates myelocytomatosis (MYC) (Ser62/Ser329), cell division cycle 25A (CDC25A), and Notch homolog 1, translocation-associated (Notch1) (Ser2152) for triggering transcriptional activation and cell cycles to promoting cancer cell proliferation. Phosphorylation by PIM also inactivates p21^Cip1/Waf1 (Thr145)/p27^Kip1 (Thr157) and BCL-2-associated agonist of cell death (BAD) (Ser112) for prohibiting cell cycle regulation and apoptosis. PIM possibly phosphorylates C-X-C chemokine recepter type 4 (CXCR4) thereby enhances chronic lymphocytic leukemia cell survival, and decreases reactive oxygen species (ROS) by regulation of Nrf2 in the hypoxic tumor cells.

Figure 2

Signaling pathways involving PIM kinase. Up-stream target proteins of PIM (proviral integration site for moloney murine leukemia virus) kinase are janus kinase/signal transducers and activators of transcriptions (JAK/STATs) and their activations cause to stimulate PIM kinase. Activated PIM kinase boosts its downstream signaling targets, such as myelocytomatosis (MYC), BCL-2-associated agonist of cell death (BAD), p21^Cip1/Waf1/p27^Kip1, and cell devision cycle 25 (CDC25), and regulates gene transcription, cell cycle progression, and apoptosis.