title: p53 acetylation enhances Taxol-induced apoptosis in human cancer cells.
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.
authors.affiliation: Research Institute National Cancer Center, 323 Ilsan-ro, Gyeonggi-do, Ilsandon-gu, Goyang-si, 410-769, Korea.
authors.forename: Jae Hyeong
authors.initials: JH
authors.lastname: Kim
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Yoon
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Seong-Yeol
authors.initials: SY
authors.lastname: Park
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Hong
authors.forename: Chang-Hun
authors.initials: CH
authors.lastname: Lee
authors.forename: Yeon-Su
authors.initials: YS
authors.lastname: Lee
authors.forename: Kyungho
authors.initials: K
authors.lastname: Choi
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
authors.forename: Kyungtae
authors.initials: K
authors.lastname: Kim
authors.forename: In-Hoo
authors.initials: IH
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel