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p53 acetylation enhances Taxol-induced apoptosis in human cancer cells

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Abstract

Microtubule inhibitors (MTIs) such as Taxol have been used for treating various malignant tumors. Although MTIs have been known to induce cell death through mitotic arrest, other mechanisms can operate in MTI-induced cell death. Especially, the role of p53 in this process has been controversial for a long time. Here we investigated the function of p53 in Taxol-induced apoptosis using p53 wild type and p53 null cancer cell lines. p53 was upregulated upon Taxol treatment in p53 wild type cells and deletion of p53 diminished Taxol-induced apoptosis. p53 target proteins including MDM2, p21, BAX, and β-isoform of PUMA were also upregulated by Taxol in p53 wild type cells. Conversely, when the wild type p53 was re-introduced into two different p53 null cancer cell lines, Taxol-induced apoptosis was enhanced. Among post-translational modifications that affect p53 stability and function, p53 acetylation, rather than phosphorylation, increased significantly in Taxol-treated cells. When acetylation was enhanced by anti-Sirt1 siRNA or an HDAC inhibitor, Taxol-induced apoptosis was enhanced, which was not observed in p53 null cells. When an acetylation-defective mutant of p53 was re-introduced to p53 null cells, apoptosis was partially reduced compared to the re-introduction of the wild type p53. Thus, p53 plays a pro-apoptotic role in Taxol-induced apoptosis and acetylation of p53 contributes to this pro-apoptotic function in response to Taxol in several human cancer cell lines, suggesting that enhancing acetylation of p53 could have potential implication for increasing the sensitivity of cancer cells to Taxol.

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Acknowledgments

We would like to thank Dr. Ja-Eun Kim (Kyunghee University, Seoul, Korea) for kindly sharing her anti-Sirt1 antibody, Dr. Xuan Liu (University of California, Riverside, USA) for providing a mutant p53 plasmid, and Tae Sik Kim for technical support on flow cytometry. We would like to give special thanks to Dr. Sun-Shin Kim, and Dr. Hye-Jin Yu for scientific discussion and Dr. J.S. Ram for critical reading during the manuscript preparation. This work was supported by grants for K.K. from National Cancer Center Korea (NCC-1110080).

Conflict of interest

The authors declare no conflicts of interest.

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Author notes

  1. Kyungho Choi

    Present address: Department of Biochemistry and Molecular Biology, Seoul National University college of Medicine, 103 Deahak-ro, Jongno-gu, Seoul, 110-799, Korea

Authors and Affiliations

  1. Research Institute National Cancer Center, 323 Ilsan-ro, Gyeonggi-do, Ilsandon-gu, Goyang-si, 410-769, Korea

    Jae Hyeong Kim, Eun-Kyung Yoon, Hye-Jin Chung, Seong-Yeol Park, Kyeong-Man Hong, Chang-Hun Lee, Yeon-Su Lee, Kyungho Choi, Kyungtae Kim & In-Hoo Kim

  2. Department of Life Science, Research Center for Woman’s Disease, Sookmyung Woman’s University, Seoul, 140-742, Korea

    Jae Hyeong Kim & Young Yang

  3. Division of Life and Phamaceutical Sciences, The graduate School, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 120-750, Korea

    Eun-Kyung Yoon

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  1. Jae Hyeong Kim
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Correspondence to Kyungtae Kim.

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Jae Hyeong Kim and Eun-Kyung Yoon contributed equally to this study.

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Kim, J.H., Yoon, EK., Chung, HJ. et al. p53 acetylation enhances Taxol-induced apoptosis in human cancer cells. Apoptosis 18, 110–120 (2013). https://doi.org/10.1007/s10495-012-0772-8

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