IL-6 Stimulates STAT3 and Pim-1 Kinase in Pancreatic Cancer Cell Lines

Block, Katherine M.; Hanke, Neale T.; Maine, Erin A.; Baker, Amanda F.

doi:10.1097/mpa.0b013e31823cdd10

Cited by 50 publications

(37 citation statements)

References 33 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In prostate inflammation, Th1 responses (IFN-γ, TNFα) and Th2 responses (IL-4, IL-5, IL-13) are activated, in addition to the expression of IL-6, IL-8 and IL-10, and NFκB activation [77]. Because IL-6, NFκB and Stat3 increase endogenous Pim1 expression, there would be an additional increase of Pim1 available in prostate tissues due to this positive feedback loop, possibly explaining an impaired immune response; Pim1 has been implicated in inflammation in several in vitro and in vivo models [78], [79]. Pim1 and Pim2 have also been shown to belong to an endogenous pathway that regulates T-cell growth and survival [80], [81].…”

Section: Discussionmentioning

confidence: 99%

Conditional Transgenic Expression of PIM1 Kinase in Prostate Induces Inflammation-Dependent Neoplasia

et al. 2013

View full text Add to dashboard Cite

The Pim proteins are a family of highly homologous protein serine/threonine kinases that have been found to be overexpressed in cancer. Elevated levels of Pim1 kinase were first discovered in human leukemia and lymphomas. However, more recently Pim1 was found to be increased in solid tumors, including pancreatic and prostate cancers, and has been proposed as a prognostic marker. Although the Pim kinases have been identified as oncogenes in transgenic models, they have weak transforming abilities on their own. However, they have been shown to greatly enhance the ability of other genes or chemical carcinogens to induce tumors. To explore the role of Pim1 in prostate cancer, we generated conditional Pim1 transgenic mice, expressed Pim1 in prostate epithelium, and analyzed the contribution of PIM1 to neoplastic initiation and progression. Accordingly, we explored the effect of PIM1 overexpression in 3 different settings: upon hormone treatment, during aging, and in combination with the absence of one Pten allele. We have found that Pim1 overexpression increased the severity of mouse prostate intraepithelial neoplasias (mPIN) moderately in all three settings. Furthermore, Pim1 overexpression, in combination with the hormone treatment, increased inflammation surrounding target tissues leading to pyelonephritis in transgenic animals. Analysis of senescence induced in these prostatic lesions showed that the lesions induced in the presence of inflammation exhibited different behavior than those induced in the absence of inflammation. While high grade prostate preneoplastic lesions, mPIN grades III and IV, in the presence of inflammation did not show any senescence markers and demonstrated high levels of Ki67 staining, untreated animals without inflammation showed senescence markers and had low levels of Ki67 staining in similar high grade lesions. Our data suggest that Pim1 might contribute to progression rather than initiation in prostate neoplasia.

show abstract

Section: Discussionmentioning

confidence: 99%

Conditional Transgenic Expression of PIM1 Kinase in Prostate Induces Inflammation-Dependent Neoplasia

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The activation of STATs by JAK‐mediated phosphorylation leads to STAT dimerization and nuclear translocation, wherein the STATs bind to specific promoter regions of the corresponding target genes and regulate their expression. ISFR/GAS sequence (Interferon gamma, IFN‐γ activation sequence) is the main binding site of STAT3 and STAT5 to the PIM1 promoter, thus, upregulating PIM1 gene expression . PIM1, in turn, inhibits the JAK/STAT pathway by binding to and activating the suppressor of cytokine signaling (SOCS) proteins, which are negative regulators of the JAK/STAT pathway (Fig.…”

Section: The Pim Kinase Familymentioning

confidence: 99%

“…ISFR/GAS sequence (Interferon gamma, IFN-γ activation sequence) is the main binding site of STAT3 and STAT5 to the PIM1 promoter, thus, upregulating PIM1 gene expression. [18][19][20] PIM1, in turn, inhibits the JAK/STAT pathway by binding to and activating the suppressor of cytokine signaling (SOCS) proteins, which are negative regulators of the JAK/STAT pathway ( Fig. 3).…”

Section: The Pim Kinase Familymentioning

confidence: 99%

The PIM Family of Serine/Threonine Kinases in Cancer

Narlik-Grassow

Blanco‐Aparicio

Carnero

2013

Medicinal Research Reviews

191

192

View full text Add to dashboard Cite

The proviral insertion site in Moloney murine leukemia virus, or PIM proteins, are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2, and PIM3) that are highly evolutionarily conserved. These proteins are regulated primarily by transcription and stability through pathways that are controlled by Janus kinase/Signal transducer and activator of transcription, JAK/STAT, transcription factors. The PIM family proteins have been found to be overexpressed in hematological malignancies and solid tumors, and their roles in these tumors were confirmed in mouse tumor models. Furthermore, the PIM family proteins have been implicated in the regulation of apoptosis, metabolism, cell cycle, and homing and migration, which has led to the postulation of these proteins as interesting targets for anticancer drug discovery. In the present work, we review the importance of PIM kinases in tumor growth and as drug targets.

show abstract

“…STAT proteins have been linked to the control of the development of hematopoietic cells involved in inflammation, and mediating the responses of target cells to inflammatory cytokines. This has been corroborated in several PIM-dependent in vitro and in vivo models4849. PIM1 appears to contribute to NFκB activation upon TNF-α activation50 through a feedback loop, while PIM1-inhibitors prevent NFκB activation and decrease iNOS production in macrophages and decrease levels of TNFα.…”

Section: Discussionmentioning

confidence: 67%

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

Jiménez-García

Lucena-Cacace

Robles‐Frías

et al. 2016

Sci Rep

View full text Add to dashboard Cite

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...

show abstract

IL-6 Stimulates STAT3 and Pim-1 Kinase in Pancreatic Cancer Cell Lines

Cited by 50 publications

References 33 publications

Conditional Transgenic Expression of PIM1 Kinase in Prostate Induces Inflammation-Dependent Neoplasia

Conditional Transgenic Expression of PIM1 Kinase in Prostate Induces Inflammation-Dependent Neoplasia

The PIM Family of Serine/Threonine Kinases in Cancer

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

Contact Info

Product

Resources

About