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EGFR-mediated hyperacetylation of tubulin induced docetaxel resistance by downregulation of HDAC6 and upregulation of MCAK and PLK1 in prostate cancer cells.
Pu, Yeong-Shiau; Huang, Chao-Yuan; Wu, Hung-Lin; Wu, Jyun-Hong; Su, Ying-Fang; Yu, Chang-Tze Ricky; Lu, Chi-Yu; Wu, Wen-Jeng; Huang, Shu-Pin; Huang, Ying-Tang; Hour, Tzyh-Chyuan.
Afiliación
  • Pu YS; Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
  • Huang CY; Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.
  • Wu HL; Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Wu JH; Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Su YF; Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Yu CR; Department of Applied Chemistry, National Chi Nan University, Nantou, Taiwan.
  • Lu CY; Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Wu WJ; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Huang SP; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • Huang YT; Department of Marine Biotechnology, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan.
  • Hour TC; Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Kaohsiung J Med Sci ; 40(1): 23-34, 2024 Jan.
Article en En | MEDLINE | ID: mdl-37916740
Docetaxel-based chemotherapy has generally been considered as one of the effective treatments for castration-resistant prostate cancer (PCa). However, clinical treatment with docetaxel often encounters a number of undesirable effects, including drug resistance. Tubulin isoforms have been previously examined for their resistance to docetaxel in many cancers, but their real mechanisms remained unclear. In this study, a series of docetaxel-resistant PC/DX cell sublines were established by chronically exposing PC3 to progressively increased concentrations of docetaxel. Western blotting results showed significantly higher expression of acetyl-tubulin, α-tubulin, ß-tubulin, γ-tubulin, and ßIII-tubulin in PC/DX25 than in parental PC3 cells. PC/DX25 with greater resistance to docetaxel had higher levels of acetyl-tubulin and mitotic centromere-associated kinesin (MCAK) than PC3 cells. This study found that docetaxel induced the expression of acetyl-tubulin and MCAK in PC3 cells at a dose- and time-dependent manner. Both mRNA and protein levels of histone deacetylase 6 (HDAC6) were significantly decreased in PC/DX25 compared with PC3 cells. PC3 increased the resistance to docetaxel by HDAC6 knockdown and Tubastatin A (HDAC6 inhibitor). Conversely, PC/DX25 reversed the sensitivity to docetaxel by MCAK knockdown. Notably, flow cytometry analysis revealed that MCAK knockdown induced significantly sub G1 fraction in PC/DX cells. Overexpression of polo-like kinase-1 increased the cell survival rate and resistance to docetaxel in PC3 cells. Moreover, epidermal growth factor receptor (EGFR) activation induced the upregulation of acetyl-tubulin in docetaxel-resistant PCa cells. These findings demonstrated that the EGFR-mediated upregulated expression of acetyl-tubulin played an important role in docetaxel-resistant PCa.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Tubulina (Proteína) Límite: Humans / Male Idioma: En Revista: Kaohsiung J Med Sci Asunto de la revista: MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: China
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Tubulina (Proteína) Límite: Humans / Male Idioma: En Revista: Kaohsiung J Med Sci Asunto de la revista: MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: China