PIM kinase (and Akt) biology and signaling in tumors

Abstract

The initiation and progression of human cancer is frequently linked to the uncontrolled activation of survival kinases. Two such pro-survival kinases that are commonly amplified in cancer are PIM and Akt. These oncogenic proteins are serine/threonine kinases that regulate tumorigenesis by phosphorylating substrates that control the cell cycle, cellular metabolism, proliferation, and survival. Growing evidence suggests that cross-talk exists between the PIM and Akt kinases, indicating that they control partially overlapping survival signaling pathways that are critical to the initiation, progression, and metastatic spread of many types of cancer. The PI3K/Akt signaling pathway is activated in many human tumors, and it is well established as a promising anticancer target. Likewise, based on the role of PIM kinases in normal and tumor tissues, it is clear that this family of kinases represents an interesting target for anticancer therapy. Pharmacological inhibition of PIM has the potential to significantly influence the efficacy of standard and targeted therapies. This review focuses on the regulation of PIM kinases, their role in tumorigenesis, and the biological impact of their interaction with the Akt signaling pathway on the efficacy of cancer therapy.

Pim Kinase Interacts with Nonstructural 5A Protein and Regulates Hepatitis C Virus Entry

“…It was reported previously that HCV transiently activates the PI3K-AKT pathway during virus entry (36). Growing evidence suggests that Pim kinases cross talk with PI3K-AKT kinases to produce synergetic effects on cell proliferation and survival signaling pathways (37)(38)(39). Therefore, we are tempted to speculate that Pim kinase might regulate HCV entry by promoting CD81 and claudin-1 receptor complex formation via PI3K-AKT signaling pathway.…”

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity

“…The provirus integration sites for Moloney murine leukemia virus (PIM) kinases are a highly conserved family of serine/threonine kinases (1,2). The PIM kinase family is composed of 3 different isoforms, PIM-1, PIM-2, and PIM-3, which share high homology at the amino acid sequences (3) and have functional redundancy (4).…”

Inhibition of autophagy enhances SMI-4a-induced growth inhibition and apoptosis of melanoma cells

“…An inhibitory effect of PIM-1 silencing on the proliferation of melanoma cells has been previously suggested [3]. SMI-4a is a small molecular highly selective PIM-1 inhibitor that has been found to block PIM-1 kinase activity in vitro and in vivo [14].…”

“…A growing body of evidence has demonstrated that atopic expression of PIM-1 in cancer cells is responsible for tumour growth and metastasis [3]. Inhibition of PIM-1 by knockdown studies can reduce proliferation and viability in preclinical models of melanoma [4].…”

“…The combination of SMI-4a and chloroquine was more efficacious than each individual agent (p < 0.01, Figure 5). 3 , the mice were randomly grouped into four groups of 6 mice each. Mice in the four groups were given orally administrations of 0.5 % MC (vehicle control), SMI-4a (15 mg/kg, po, qid), chloroquine (30 mg/kg, po, qid), or SMI-4a plus chloroquine, respectively.…”