Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer.
J Clin Invest
; 120(10): 3594-605, 2010 Oct.
Article
in En
| MEDLINE
| ID: mdl-20811155
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Testicular Neoplasms
/
Cisplatin
/
Cytoplasm
/
Cyclin-Dependent Kinase Inhibitor p21
/
Antineoplastic Agents
Limits:
Humans
/
Male
Language:
En
Journal:
J Clin Invest
Year:
2010
Document type:
Article
Affiliation country:
Netherlands
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA