Sulforaphane induces autophagy by inhibition of HDAC6-mediated PTEN activation in triple negative breast cancer cells

  • Life Sci. 2018 Nov 15;213:149-157. doi: 10.1016/j.lfs.2018.10.034.
Fan Yang  1 ,  Faling Wang  2 ,  Yuni Liu  3 ,  Shien Wang  3 ,  Xin Li  1 ,  Yi Huang  4 ,  Yan Xia  5 ,  Chunyu Cao  6
Affiliations
  • 1. The Second People's Hospital of China Three Gorges University, Yichang 443002, China.
  • 2. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang 443002, China; Yichang Center for Disease Control and Prevention, Yichang 443002, China.
  • 3. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang 443002, China.
  • 4. Women's Cancer Research Center of UPMC Hillman Cancer Center, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 5. Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic diseases(Hubei University for Nationalities), Enshi 445000, China. Electronic address: [email protected].
  • 6. Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang 443002, China. Electronic address: [email protected].
PMID: 30352240 DOI: 10.1016/j.lfs.2018.10.034
Abstract

Aims: To study the underlying mechanisms of sulforaphane, a natural histone deacetylase (HDAC) inhibitor, in inhibiting triple negative breast Cancer cells growth and the therapeutic effects of combination of sulforaphane and doxorubicin in TNBC treatment.

Materials and methods: The antineoplastic activity of sulforaphane was evaluated in MDA-MB-231, BT549 and MDA-MB-468 cells with MTT assay. Cell Apoptosis was detected with Annexin V/PI double staining by Flow cytometry. Cell Autophagy was detected with fluorescence microscope. The effects of Sulforaphane and Doxorubicin combination treatments on cells growth were determined with Chou-Talalay median effect/combination index (CI) model. mRNA and protein expression of genes were assayed respectively with Real-Time PCR and Western bloting. Protein-protein interaction was detected with co-immunoprecipation. Gene knock-down was performed with small interfere RNA. In vivo assay of combinational treatment with sulforaphane and doxorubicin was investigated in athymic nude mice bearing MDA-MB-231 xenografts.

Key findings: Results showed that sulforaphane inhibited cell growth and induced Autophagy in MDA-MB-231, BT549 and MDA-MB-468 cells. Further study demonstrated that sulforaphane induced Autophagy by down-regulating expression of HDAC6, which resulted in increased membrane translocation and acetylation modification of Phosphatase and tensin homolog (PTEN). Sulforaphane and doxorubicin combination exhibited a synergistic inhibition on TNBC cells growth. In nude mice, the combination of sulforaphane and doxorubicin displayed a greater inhibitory effect on MDA-MB-231 xenografts growth as compared to either treatment alone.

Significance: Our study suggested that induction of Autophagy by targeting HDAC6 in combination with chemotherapeutic reagent may provide a novel strategy for TNBC therapy.

Keywords
Autophagy; Histone deacetylase 6; Phosphatase and tensin homolog; Sulforaphane; Triple negative breast cancer.
Products