Resistance to cytotoxic chemotherapy-induced apoptosis in human prostate cancer cells is associated with intracellular clusterin expression.
We recently reported the powerful antiapoptotic activity of clusterin against various apoptotic stimuli in prostate cancer model systems; however, the precise mode of clusterin action in target cells remains largely unknown. In the present study, we therefore investigated whether intracellular or extracellular action of clusterin plays a crucial role in cytotoxic chemotherapy-induced apoptosis in androgen-independent human prostate cancer PC3 cells, which express a high level of clusterin. The sensitivity of PC3 cells to paclitaxel was increased by pretreatment with monoclonal antibody (mAb) to clusterin or antisense (AS) oligodeoxynucleotide (ODN) targeting the clusterin gene in a dose-dependent manner at up to 50 microg/ml or 1 microM, respectively. However, clusterin mAb failed to further enhance the sensitivity to paclitaxel of PC3 cells simultaneously treated with 1 microM AS clusterin ODN, whereas AS clusterin ODN further induced the apoptosis of cells treated with 50 microg/ml clusterin mAb. Moreover, the effects of clusterin mAb and AS clusterin ODN on PC3 cells were not reversed by additional treatment with exogenous recombinant clusterin protein. These findings suggest that the sensitivity of PC3 cells to paclitaxel-induced cytotoxicity may be regulated by the intracellular rather than extracellular level of clusterin.
Miyake
Hideaki
H
Department of Urology, Hyogo Medical Center for Adults, Akashi 673-8558, Japan. hideakimiyake@hotmail.com
Hara
Isao
I
Kamidono
Sadao
S
Gleave
Martin E
ME
Eto
Hiroshi
H
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D051152:Clusterin; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017239:Paclitaxel / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; C495242:CLU protein, human; D051152:Clusterin; D004338:Drug Combinations; D006023:Glycoproteins; D018832:Molecular Chaperones; D016376:Oligonucleotides, Antisense; D017239:Paclitaxel