The BH3-only protein, PUMA, is involved in oxaliplatin-induced apoptosis in colon cancer cells

Xinying Wang, Ming Li, Jide Wang, Chung Man Yeung, Hongquan Zhang, Hsiang fu Kung, Bo Jiang, Marie Chia-mi Lin

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Oxaliplatin, the first line chemotherapeutic of colon cancer, induces damage to tumors via induction of apoptosis. PUMA (p53 up-regulate modulator of apoptosis) is an important pro-apoptotic member of Bcl-2 family and regulated mainly by p53. Here we investigated the role of PUMA in oxalipaltin-induced apoptosis and the potential mechanism. We showed that oxaliplatin-induced PUMA expression in a time- and dose-dependent manner and suppression of PUMA expression by stable transfecting anti-sense PUMA plasmid decreased oxaliplatin-induced apoptosis in colon cancer cells. By abrogating the function of p53, we further demonstrated that the induction was p53-independent. We also found that oxaliplatin could inactivate ERK and suppression of ERK activity by its specific inhibitor (PD98059), and dominant negative plasmid (DN-MEK1) enhanced the oxaliplatin-induced PUMA expression and apoptosis in a p53-independent manner. Taken together, our data suggest that PUMA plays an important role in oxaliplatin-induced apoptosis and the induction could be both p53-dependent and p53-independent. Moreover, PUMA expression and apoptosis in oxaliplatin-treated colon cancer cells could be regulated partly by ERK inactivation. Identification of the molecular components involved in regulating the cellular sensitivity to oxaliplatin may provide potential targets for development of novel compounds that may be useful in enhancement of oxaliplatin cytotoxicity in p53 deficient colon cancer.

Original languageEnglish (US)
Pages (from-to)1540-1550
Number of pages11
JournalBiochemical Pharmacology
Volume71
Issue number11
DOIs
StatePublished - May 28 2006
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Dr. Thijn R. Brummelkamp for providing the pSUPER-p53 plasmid. This work was supported by the Science and Technology Program of Guangdong province, China (2002C30307). This work was also supported in part by an AoE scheme of UGC and grants from the Research Grants Council of the Hong Kong Special Administrative Region, China (HKU 7243/02M to MCL) and grants from Li Ka Shing Institute of Health Sciences, Hong Kong, China (to HFK).

Keywords

  • Apoptosis
  • Colon cancer
  • ERK
  • Oxaliplatin
  • PUMA
  • p53

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