TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth.
BACKGROUND
Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer.


RESULTS
By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen-depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens.


CONCLUSIONS
Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease.
Department of Molecular Microbiology and Immunology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America. hyeongnj@usc.edu
Joseph H
JH
Jeong
Ayesha
A
Bhatia
Zsolt
Z
Toth
Soohwan
S
Oh
Kyung-Soo
KS
Inn
Chun-Peng
CP
Liao
Pradip
P
Roy-Burman
Jonathan
J
Melamed
Gerhard A
GA
Coetzee
Jae U
JU
Jung
D000728:Androgens; D000818:Animals; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
D000728:Androgens; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human
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