Journal
BIOCHEMICAL PHARMACOLOGY
Volume 80, Issue 9, Pages 1326-1334Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.07.025
Keywords
Plk; Cisplatin; p73 alpha; A431 cells; Squamous cell carcinoma
Categories
Funding
- Council of Scientific & Industrial Research (India)
- Indian Council of Medical Research (India)
- CSIR (India) [SIP-08]
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Polo-like kinase 1 (Plk1), a critical regulator of mitotic entry, progression and exit, has been shown to be involved in a variety of cancers and thus is becoming an attractive target for cancer management. In case of DNA damage, Plk1 not only inhibits p53 independent apoptosis by dysfunctioning p73 alpha but also allows cells to recover from growth arrest. Here, we showed the effects of knocking down plk1 gene through small interference RNA (siRNA) on cell cycle progression, proliferation and chemosensitivity of p53 mutant A431 cells to cisplatin (CDDP). The expression of Plk1 was measured by RT-PCR and Western blotting. Anti-proliferative response accompanied with cell cycle arrest in G(2)/M phase and induction of cell death was recorded following Plk1 knockdown. Furthermore, cells following knockdown of Plk1, which induced increase of Cyclin B1, p-Cdc2 and p73 alpha with a decrease in p-Cdc25C, were more sensitive to CDDP. CDDP treatment induced nuclear translocation and co-localization of Plk1 with p73 alpha whereas combination of CDDP and Plk1 siRNA upregulated the expression of p73 alpha protein in a synergistic manner thereby leading to an increase up to similar to 5 folds in CDDP-induced cell death. The increase in caspase-3 activity indicated apoptosis as a contributor in the total cell death. Conclusively, plk1 gene silencing can enhance the sensitivity of A431 cells to low doses of CDDP by upregulating p73 alpha expression and thus can be a revolutionary approach in cancer chemotherapy. (C) 2010 Elsevier Inc. All rights reserved.
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