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p53 and p21 Determine the Sensitivity of Noscapine-Induced Apoptosis in Colon Cancer Cells

¹ Department of Cell Biology and ² Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and ³ Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China

Requests for reprints: Harish C. Joshi or Ritu Aneja, Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322. Phone: 404-727-0445; Fax: 404-727-6256; E-mail: joshi{at}cellbio.emory.edu or raneja{at}emory.edu.

We have previously discovered the naturally occurring antitussive alkaloid noscapine as a tubulin-binding agent that attenuates microtubule dynamics and arrests mammalian cells at mitosis via activation of the c-Jun NH₂-terminal kinase pathway. It is well established that the p53 protein plays a crucial role in the control of tumor cell response to chemotherapeutic agents and DNA-damaging agents; however, the relationship between p53-driven genes and drug sensitivity remains controversial. In this study, we compared chemosensitivity, cell cycle distribution, and apoptosis on noscapine treatment in four cell lines derived from the colorectal carcinoma HCT116 cells: p53^+/+ (p53-wt), p53^–/– (p53-null), p21^–/– (p21-null), and BAX^–/– (BAX-null). Using these isogenic variants, we investigated the roles of p53, BAX, and p21 in the cellular response to treatment with noscapine. Our results show that noscapine treatment increases the expression of p53 over time in cells with wild-type p53 status. This increase in p53 is associated with an increased apoptotic BAX/Bcl-2 ratio consistent with increased sensitivity of these cells to apoptotic stimuli. Conversely, loss of p53 and p21 alleles had a counter effect on both BAX and Bcl-2 expression and the p53-null and p21-null cells were significantly resistant to the antiproliferative and apoptotic effects of noscapine. All but the p53-null cells displayed p53 protein accumulation in a time-dependent manner on noscapine treatment. Interestingly, despite increased levels of p53, p21-null cells were resistant to apoptosis, suggesting a proapoptotic role of p21 and implying that p53 is a necessary but not sufficient condition for noscapine-mediated apoptosis. [Cancer Res 2007;67(8):3862–70]

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