The role of PIM1/PIM2 kinases in tumors of the male reproductive system

Abstract

The PIM family of serine/threonine kinases has three highly conserved isoforms (PIM1, PIM2 and PIM3). PIM proteins are regulated through transcription and stability by JAK/STAT pathways and are overexpressed in hematological malignancies and solid tumors. The PIM kinases possess weak oncogenic abilities, but enhance other genes or chemical carcinogens to induce tumors. We generated conditional transgenic mice that overexpress PIM1 or PIM2 in male reproductive organs and analyzed their contribution to tumorigenesis. We found an increase in alterations of sexual organs and hyperplasia in the transgenic mice correlating with inflammation. We also found that PIM1/2 are overexpressed in a subset of human male germ cells and prostate tumors correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression is a common feature of male reproductive organs tumors, which provoke tissue alterations and a large inflammatory response that may act synergistically during the process of tumorigenesis. There is also a correlation with markers of cancer stem cells, which may contribute to the therapy resistance found in tumors overexpressing PIM kinases.The Proviral Insertion site in Moloney murine leukemia virus proteins (PIM) are a highly evolutionarily conserved family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2 and PIM3). These proteins are regulated primarily through transcription and stability by pathways that are controlled by JAK/STAT transcription factors 1,2 , cytokines, and growth factors involved in hematopoiesis, such as interleukins, GM-CSF and G-CSF 3,4 . In addition, nuclear factor-κ B, Jak-signal transducer and activator of transcription (STAT), ETS-related gene and hypoxia-inducible factor-1α are the primary pathways that induce PIM1 upregulation [5][6][7][8] . Furthermore, the stability and function of PIM kinases depend on their interaction with heat shock protein (Hsp) 90 9,10 , a chaperone involved in the folding and stabilization of different molecules. Hsp90 has been shown to not only to protect from ubiquitin-dependent proteasomal degradation but has also been shown to maintain the proper conformation of PIM proteins 10 . The downstream targets of PIM1 signaling are typically regulated by direct phosphorylation by PIM1. Thus far, approximately 30 substrates have been shown to interact with and be phosphorylated by PIM1. Through phosphorylation of target proteins, PIM1 plays essential roles in the regulation of the cell cycle, cell proliferation, anti-apoptosis, multiple drug resistance, chromatin remodeling, protein translation, energy metabolism, and the stress response [11][12][13] . It has been suggested that PIM family members are weak oncogenes that can contribute to tumorigenesis by selectively enhancing tumorigenic properties 1,2 . However, PIM family members have also been shown to increase the capacity of other genes or chemical carcinogens to induce tumors [14][15][16] . The magnitude of the effect varies depending on...

Conservation of epigenetic regulation by the MLL3/4 tumour suppressor in planarian pluripotent stem cells

“…Overexpression of the cell fate decisions determinant Elf5 is a known driving force behind breast cancer progression and metastasis 64 . The PIM family of proteins is involved in the integration of growth and survival signals 65 and their overexpression has been associated with hematological malignancies and solid tumours 66 . Inhibition of PI M2 is a promising avenue for the treatment of multiple myeloma 65 .…”

“…As proof of principle that genes mis-regulated by LPT (RNAi) directly contributed to the phenotype, we performed double RNAi experiments. Planarian homologs of the oncogene pim-2 , called Smed-pim-2 and Smed-pim-2-like , that were overexpressed in stem cells following LPT (RNAi), were chosen as likely candidates, based on previous data on the roles of these genes from mammals 66-70 . We found that double RNAi with pim-2-like , was able to ameliorate LPT loss of function over-proliferation and outgrowth phenotypes induced by LPT (RNAi).…”

Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumour fate

“…In addition to already well-established markers of pluripotency, we found PIM2 and OTX2 to be SOX2 target genes in ECs. Overexpression of PIM1 and PIM2 in mice resulted in an increase in inflammatory signatures as well as an overall higher cell proliferation rate in testicular tissues 33 . Both PIM2 and OTX2 are overexpressed in TGCT, but not much is known about their role in human TGCTs.…”

“…Data 3 upon request). PIM2 is a proto-oncogene regulating survival and proliferation 33 . We found that PIM2 is highly expressed in 2102EP and TCam-2 cells, but weakly in the Sertoli cell line FS1 and adult fibroblasts (MPAF) (Supp.…”

The role of Pim-2 in apoptotic signal transduction pathway of hepatocellular carcinoma

“…10,12 Pim-2 has also been proved to be relevant to the tumorigenesis of hepatocellular carcinoma (HCC), but up to now there is little study of the relationship between Pim-2 and apoptosis signal transduction pathway of hepatoma cell. 13,14 Liver has special structure and function in the body and hepatocyte is rich in blood supply and cytokines.…”