Inhibition of HER-kinase activation prevents ERK-mediated degradation of PPARgamma.
R-etodolac, a nonsteroidal anti-inflammatory drug, inhibits the progression of CWRSA6 androgen-independent and LuCaP-35 androgen-dependent prostate cancer xenograft growth through downregulation of cyclin D1 expression via the PPARgamma pathway. PPARgamma protein degradation, observed post-R-etodolac treatment, resulted from phospho-MAP kinase (p44/42) induction by R-etodolac negatively regulating PPARgamma function. Negative regulation of PPARgamma was overcome by a combination regimen of R-etodolac with the HER-kinase axis inhibitor, rhuMab 2C4, which demonstrated an additive antitumor effect. We further show that the inhibition of HER-kinase activity by rhuMab 2C4 is sufficient to inhibit PPARgamma protein degradation. This study introduces a novel concept of an in vivo crosstalk between the HER-kinase axis and PPARgamma pathways, ultimately leading to negative regulation of PPARgamma activity and tumor growth inhibition.
Hedvat
Michael
M
Louis Warschaw Prostate Cancer Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 1001E, Los Angeles, CA 90048, USA.
Jain
Anjali
A
Carson
Dennis A
DA
Leoni
Lorenzo M
LM
Huang
Ganghua
G
Holden
Stuart
S
Lu
Desheng
D
Corr
Maripat
M
Fox
William
W
Agus
David B
DB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001391:Azo Compounds / Q000494:pharmacology; D015153:Blotting, Western; D018955:CD36 Antigens / Q000096:biosynthesis; D002460:Cell Line; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000494:pharmacology; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D017308:Etodolac / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D050356:Lipid Metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D009000:Monocytes / Q000378:metabolism; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000473:pathology; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D000970:Antineoplastic Agents; D001391:Azo Compounds; D018955:CD36 Antigens; D004396:Coloring Agents; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019938:Cyclin D1; D017308:Etodolac; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; C011049:oil red O