E2F1 is a positive regulator of cell cycle progression and also a potent inducer of apoptosis, especially when activated by DNA damage. We identified E2F1-inducible microRNAs (miRNAs) by microarray hybridization and found that the levels of miRNAs 449a and 449b, as well as their host gene CDC20B, are strongly upregulated by E2F1. High miR-449 levels were found in testes, lung, and trachea, but not in testicular and other cancer cells. MiR-449a/b structurally resemble the p53-inducible miRNA 34 family. In agreement with a putative tumor-suppressive role, miR-449a as well as miR-34a reduced proliferation and strongly promoted apoptosis by at least partially p53-independent mechanisms. Both miRNAs reduced the levels of CDK6, implying miR-449 in a negative feedback mechanism for E2F1. Moreover, miR-449a and miR-34a diminished the deacetylase Sirt1 and augmented p53 acetylation. We propose that both miRNAs provide a twofold safety mechanism to avoid excessive E2F1-induced proliferation by cell cycle arrest and by apoptosis. While responding to different transactivators, miRNAs 449 and 34 each repress E2F1, but promote p53 activity, allowing efficient cross-talk between two major DNA damage-responsive gene regulators.
Cisplatin has become one of the most commonly prescribed cytotoxic chemotherapeutic agents. Unfortunately, the cure rate is low due to the development or outgrowth of cisplatin-resistant cells which repopulate tumors, resulting in patient death. We reported previously that the calcium channel blocker nifedipine enhances the antitumour actions of cisplatin (cis-diamminedichloroplatinum (II] against murine tumors which are inherently cisplatin-sensitive (B16a) or inherently cisplatin-resistant (3LL). We have developed an induced cisplatin-resistant tumor variant (B16a-Pt) that is 30 times more resistant to cisplatin than its cisplatin-sensitive parent line. In short-term studies, we report that nifedipine significantly enhanced the cytotoxicity of cisplatin against primary B16a-Pt tumors and their spontaneous pulmonary metastases. In long term studies, we report that combination therapy with nifedipine and cisplatin results in significantly enhanced survival.
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