Cell cycle arrest and cytochrome c-mediated apoptotic induction by MCS-5A is associated with up-regulation of p16INK4a in HL-60 cells |
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Authors: | Bu Young Choi Chul-Hoon Lee |
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Affiliation: | 1. Department of Molecular Biology & Pharmacology, C & C Research Lab., Kyunggi-Do 445-970, Republic of Korea;2. Department of Medical Genetics, College of Medicine, Hanyang University, Seoul 133-791, Republic of Korea |
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Abstract: | MCS-5A, an analog of sangivamycin, selectively inhibits the cyclin-dependent kinases CDK1 and 4 in HL-60 cells in vitro (IC50: 9.6 and 8.8 μΜ, respectively), while weakly inhibiting other housekeeping protein kinases. MCS-5A effectively induces HL-60 cell cycle arrest at the G1 and G2/M phases through direct inhibition of CDK1 and 4 activity. In addition, elevated expression of p16INK4a and a reduction in the level of hyperphosphorylated pRb showed that 3 μΜ MCS-5A also induces p16INK4a-mediated cell cycle arrest at the G1 phase. Furthermore, apoptotic induction in MCS-5A-treated HL-60 cells is associated with the release of cytochrome c from mitochondria, which, in turn, results in the activation of procaspase-8, -9 and -3, and the cleavage of poly(ADP-ribose) polymerase (PARP). In addition, the involvement of p16INK4a in this apoptotic induction was demonstrated using A549 cells with a homozygous deletion of p16INK4a. Based on these results, we conclude that MCS-5A is a candidate therapeutic agent for the treatment of human promyelocytic leukemia via the up-regulation of p16INK4a. |
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