Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer.
Platinum-based chemotherapies such as cisplatin are used as first-line treatment for many cancers. Although there is often a high initial responsiveness, the majority of patients eventually relapse with platinum-resistant disease. For example, a subset of testicular cancer patients still die even though testicular cancer is considered a paradigm of cisplatin-sensitive solid tumors, but the mechanisms of chemoresistance remain elusive. Here, we have shown that one key determinant of cisplatin-resistance in testicular embryonal carcinoma (EC) is high cytoplasmic expression of the cyclin-dependent kinase (CDK) inhibitor p21. The EC component of the majority of refractory testicular cancer patients exhibited high cytoplasmic p21 expression, which protected EC cell lines against cisplatin-induced apoptosis via CDK2 inhibition. Localization of p21 in the cytoplasm was critical for cisplatin resistance, since relocalization of p21 to the nucleus by Akt inhibition sensitized EC cell lines to cisplatin. We also demonstrated in EC cell lines and human tumor tissue that high cytoplasmic p21 expression and cisplatin resistance of EC were inversely associated with the expression of Oct4 and miR-106b seed family members. Thus, targeting cytoplasmic p21, including by modulation of the Oct4/miR-106b/p21 pathway, may offer new strategies for the treatment of chemoresistant testicular and other types of cancer.
Koster
Roelof
R
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
di Pietro
Alessandra
A
Timmer-Bosscha
Hetty
H
Gibcus
Johan H
JH
van den Berg
Anke
A
Suurmeijer
Albert J
AJ
Bischoff
Rainer
R
Gietema
Jourik A
JA
de Jong
Steven
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis*; D003593:Cytoplasm / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D050814:Octamer Transcription Factor-3 / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002867:Chromones; D050759:Cyclin-Dependent Kinase Inhibitor p21; C542541:MIRN106 microRNA, human; D035683:MicroRNAs; D009025:Morpholines; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D002945:Cisplatin
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