PIM1 Kinase as a Target in Prostate Cancer: Roles in Tumorigenesis, Castration Resistance, and Docetaxel Resistance
Sheldon L. Holder and Sarki A. Abdulkadir
Affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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.
Keywords: Androgen receptor, JAK, MYC, PIM1, prostate cancer, STAT, tumorigenesis.
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