The Pim protein kinases regulate energy metabolism and cell growth

Abstract

The serine/threonine Pim kinases are overexpressed in solid cancers and hematologic malignancies and promote cell growth and survival. Here, we find that a novel Pim kinase inhibitor, SMI-4a, or Pim-1 siRNA blocked the rapamycin-sensitive mammalian target of rapamycin (mTORC1) activity by stimulating the phosphorylation and thus activating the mTORC1 negative regulator AMP-dependent protein kinase (AMPK). Mouse embryonic fibroblasts (MEFs) deficient for all three Pim kinases [triple knockout (TKO) MEFs] demonstrated activated AMPK driven by elevated ratios of AMP∶ATP relative to wild-type MEFs. Consistent with these findings, TKO MEFs were found to grow slowly in culture and have decreased rates of protein synthesis secondary to a diminished amount of 5′-cap-dependent translation. Pim-3 expression alone in TKO MEFs was sufficient to reverse AMPK activation, increase protein synthesis, and drive MEF growth similar to wild type. Pim-3 expression was found to markedly increase the protein levels of both c-Myc and the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), enzymes capable of regulating glycolysis and mitochondrial biogenesis, which were diminished in TKO MEFs. Overexpression of PGC-1α in TKO MEFs elevated ATP levels and inhibited the activation of AMPK. These results demonstrate the Pim kinase-mediated control of energy metabolism and thus regulation of AMPK activity. We identify an important role for Pim-3 in modulating c-Myc and PGC-1α protein levels and cell growth.

Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells

“…26 PIM-1 phosphorylates its downstream target, Bad, which prevents the association of Bad with Bcl2 and Bcl-xl, thereby reversing Bad-induced cell apoptosis. [27][28][29] Knockdown of PIM-1 by siRNA down-regulated phospho-Bad ( Figure 3E), confirming the PIM-1/Bad signaling axis in MM.1S MM cell line. Furthermore, both miR33b overexpression and MLN2238 treatment led to decreases in phospho-Bad in the MM.1S cell line ( Figure 3F).…”

A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

“…Moreover, Pim-2 overexpression in HCT116 cells leads to enhanced phosphorylation of p21 to increase its stability (41). Furthermore, Pim-3 can augment protein synthesis (13) and regulate transcriptional activity of Myc (30). However, overexpression or ablation of Pim-3 failed to induce any changes in TCTP protein expression or phospho-TCTP ser46 levels.…”

“…We also demonstrated that Pim-3 can promote tumor growth and angiogenesis by stimulating the VEGF pathway (12). Furthermore, Pim-3 modulates Myc activity to promote tumorigenesis (13).…”

Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells

“…Respiration-A recent study has shown that PIM1 and PIM3 regulate energy metabolism and cell growth (39). Because PIM2 interacts with PKM2, which regulates glycolysis in cancer cells, we hypothesize that PIM2 regulation of glycolysis depends on PKM2.…”