Role of XIAP in the malignant phenotype of transitional cell cancer (TCC) and therapeutic activity of XIAP antisense oligonucleotides against multidrug-resistant TCC in vitro.
XIAP directly inhibits executor caspases, making it the most downstream antiapoptotic molecule. Here, we examined the expression and function of XIAP in normal urothelium and TCC. We also examined the therapeutic effect of xiap AS PODN on the cell cycle and apoptosis of multidrug-resistant T24 bladder cancer cells. XIAP was moderately expressed in normal transitional epithelium with prominent expression on the superficial layer cells. Seventy-nine of 108 (73.15%) tumor samples were positive for XIAP protein, but XIAP positivity was not correlated with tumor stage or grade. Moreover, 4 bladder cancer cell lines (SCaBER, HT1376, T24 and RT4) expressed similar levels of XIAP. xiap AS PODN dose-dependently reduced the XIAP protein level and induced apoptosis, leading to decreased cell viability by 87%. Combined administration with doxorubicin resulted in marked cytotoxicity due to escalation of apoptosis. Overexpression of XIAP in T24 cells resulted in a modest but statistically significant (p < 0.01) survival advantage compared to parental cells. Thus, XIAP expression may be critical for maintaining the viability and drug resistance of TCC, and endogenous XIAP levels are sufficient to protect cells from apoptosis. Our results suggest that XIAP may play an important role early in human TCC carcinogenesis. xiap AS may be a candidate for use as a cancer therapy for overcoming drug resistance in highly malignant TCC.
Bilim
Vladimir
V
Division of Molecular Oncology, Department of Signal Transduction Research, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
Kasahara
Takashi
T
Hara
Noboru
N
Takahashi
Kota
K
Tomita
Yoshihiko
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D013873:Thionucleotides / Q000627:therapeutic use; D014162:Transfection; D014407:Tumor Cells, Cultured; D014571:Urologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D011506:Proteins; D013873:Thionucleotides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D004317:Doxorubicin; D020169:Caspases