Modulation of mitogen-activated protein kinase cascades by differentiation-1 protein: acquired drug resistance of hormone independent prostate cancer cells.
OBJECTIVE
The inhibitor of differentiation-1 protein (Id-1) is over expressed in multidrug resistance prostate cancer cells. We determined the effect of Id-1 expression and its underlying pathways on the development of multidrug resistance in prostate cancer.


METHODS
AT3 cells were transfected with the Id-1 gene or a blank vector. Id-1 mRNA expression was determined by reverse transcriptase-polymerase chain reaction and Id-1 protein content was detected by immunoblot and flow cytometry. Cellular cytotoxicity was determined by MTT (microculture 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay (Sigma Chemical Co., St. Louis, Missouri). The activation and expression of mitogen-activated protein kinase (MAPK) were measured by transactivation assay and Western blotting, respectively.


RESULTS
Id-1 overproduction drove AT3 cells to become resistant to chemotherapeutic agents but did not induce mdr-1 gene expression. The p38MAPK and c-jun N-terminal kinase (JNK) pathways were suppressed, which correlated with increased Id-1 expression. No significant change in extracellular signal-regulated kinase (ERK) activation was observed in Id-1 transfectants compared with that of AT3 or vector control. Treatment of Id-1 expressing cells with p38MAPK and JNK inhibitors resulted in decreased doxorubicin induced apoptosis. In contrast, Id-1 expressing cells treated with ERK inhibitor made cells more sensitive to drug induced apoptosis.


CONCLUSIONS
Up-regulation of Id-1 was found in prostate cancer multidrug resistant cells. Sustained ERK activation, and JNK and p38MAPK inhibition by Id-1 in cells may confer drug resistance. These changes in MAPKs could be a mechanism for the acquisition of multidrug resistance in prostate cancer.
Lin
Jau-Chen
JC
Graduate Institute of Life Sciences, National Defense Medical Center, National Defense University, Division of Urology, Department of Surgery, Taipei, Taiwan, Republic of China.
Chang
Sun-Yran
SY
Hsieh
Dar-Shih
DS
Lee
Chi-Feng
CF
Yu
Dah-Shyong
DS
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D051798:Inhibitor of Differentiation Protein 1; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; C497454:ID1 protein, rat; D051798:Inhibitor of Differentiation Protein 1; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases