The association of CCND1 overexpression and cisplatin resistance in testicular germ cell tumors and other cancers.
Development of chemoresistance limits the clinical efficiency of platinum-based therapy. Although many resistance mechanisms have been demonstrated, genetic/molecular alterations responsible for drug resistance in the majority of clinical cases have not been identified. We analyzed three pairs of testicular germ cell tumor cell lines using Affymetrix expression microarrays and revealed a limited number of differentially expressed genes across the cell lines when comparing the parental and resistant cells. Among them, CCND1 was the most significantly differentially expressed gene. Analysis of testicular germ cell tumor clinical samples by quantitative reverse transcription PCR analysis revealed that overall expression of CCND1 was significantly higher in resistant cases compared with sensitive samples (P < 0.0001). We also found that CCND1 was dramatically overexpressed both in induced and intrinsically resistant samples of ovarian and prostate cancer. Finally combined CCND1 knockdown using small-interfering RNA and cisplatin treatment inhibited cell growth in vitro significantly more effectively than any of these single treatments. Therefore, deregulation of CCND1 may be a major cause of cisplatin resistance in testicular germ cell tumors and may also be implicated in ovarian and prostate cancers. CCND1 could be potentially used as a marker for treatment stratification and as a molecular target to improve the treatment of platinum-resistant tumors.
Noel
Elodie E
EE
Medical Oncology Centre, Cancer Institute, Barts and London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK.
Yeste-Velasco
Marc
M
Mao
Xueying
X
Perry
Jackie
J
Kudahetti
Sakunthala C
SC
Li
Ningfeng F
NF
Sharp
Swee
S
Chaplin
Tracy
T
Xue
Liyan
L
McIntyre
Alan
A
Shan
Ling
L
Powles
Thomas
T
Oliver
R Tim D
RT
Young
Bryan D
BD
Shipley
Janet
J
Berney
Daniel M
DM
Joel
Simon P
SP
Lu
Yong-Jie
YJ
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use*; D055028:Comparative Genomic Hybridization; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D019938:Cyclin D1; D002945:Cisplatin
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