TY - JOUR
T1 - PIM1 kinase as a target in prostate cancer
T2 - Roles in tumorigenesis, castration resistance, and docetaxel resistance
AU - Holder, Sheldon L.
AU - Abdulkadir, Sarki A.
N1 - Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2014
Y1 - 2014
N2 - PIM1 kinase is a serine/threonine kinase that has been shown to be overexpressed in multiple human malignancies, including prostate cancer. PIM1 phosphorylates multiple cellular substrates to inhibit apoptosis and promote cell cycle progression. Increased PIM1 can also facilitate genomic instability to promote neoplastic processes. PIM1 kinase is overexpressed in high-grade prostate intraepithelial neoplasia and in prostate cancer compared to normal prostatic tissue and benign prostate hyperplasia. Elevated PIM1 levels have been shown to be the direct result of oncogenic fusion proteins and active signal transduction pathways. In vitro and in vivo mouse studies indicate that PIM1 is weakly tumorigenic but synergizes dramatically when coexpressed with MYC. PIM1 kinase can also phosphorylate the androgen receptor (AR), thereby regulating AR degradation and function, in a low androgen environment. This finding implicates PIM1 in castration -resistant prostate cancer. Furthermore, expression of PIM1 has been shown to be increased in prostate tissue after docetaxel exposure, conferring partial resistance to docetaxel. Correlatively, decreased PIM1 levels sensitize prostate cancer cells to docetaxel treatment. Thus, PIM1 may be a target in docetaxel resistant disease. In summary, PIM1 kinase is involved in prostate tumorigenesis, castration resistance, and docetaxel resistance. Several PIM1 kinase inhibitors have been reported and are in varied stages of drug development. PIM1 is involved in multiple processes in the development and propagation of prostate cancer, thus a PIM1 kinase inhibitor may serve as an effective therapeutic agent in this prevalent disease.
AB - PIM1 kinase is a serine/threonine kinase that has been shown to be overexpressed in multiple human malignancies, including prostate cancer. PIM1 phosphorylates multiple cellular substrates to inhibit apoptosis and promote cell cycle progression. Increased PIM1 can also facilitate genomic instability to promote neoplastic processes. PIM1 kinase is overexpressed in high-grade prostate intraepithelial neoplasia and in prostate cancer compared to normal prostatic tissue and benign prostate hyperplasia. Elevated PIM1 levels have been shown to be the direct result of oncogenic fusion proteins and active signal transduction pathways. In vitro and in vivo mouse studies indicate that PIM1 is weakly tumorigenic but synergizes dramatically when coexpressed with MYC. PIM1 kinase can also phosphorylate the androgen receptor (AR), thereby regulating AR degradation and function, in a low androgen environment. This finding implicates PIM1 in castration -resistant prostate cancer. Furthermore, expression of PIM1 has been shown to be increased in prostate tissue after docetaxel exposure, conferring partial resistance to docetaxel. Correlatively, decreased PIM1 levels sensitize prostate cancer cells to docetaxel treatment. Thus, PIM1 may be a target in docetaxel resistant disease. In summary, PIM1 kinase is involved in prostate tumorigenesis, castration resistance, and docetaxel resistance. Several PIM1 kinase inhibitors have been reported and are in varied stages of drug development. PIM1 is involved in multiple processes in the development and propagation of prostate cancer, thus a PIM1 kinase inhibitor may serve as an effective therapeutic agent in this prevalent disease.
KW - Androgen receptor
KW - JAK
KW - MYC
KW - PIM1
KW - Prostate cancer
KW - STAT
KW - Tumorigenesis
UR - http://www.scopus.com/inward/record.url?scp=84896325732&partnerID=8YFLogxK
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U2 - 10.2174/1568009613666131126113854
DO - 10.2174/1568009613666131126113854
M3 - Article
C2 - 24274399
AN - SCOPUS:84896325732
SN - 1568-0096
VL - 14
SP - 105
EP - 114
JO - Current Cancer Drug Targets
JF - Current Cancer Drug Targets
IS - 2
ER -