Format

Send to

Choose Destination
Life Sci. 2018 Nov 15;213:149-157. doi: 10.1016/j.lfs.2018.10.034. Epub 2018 Oct 20.

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

Author information

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: xiayanyu@hotmail.com.
6
Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College, China Three Gorges University, Yichang 443002, China. Electronic address: caocy@ctgu.edu.cn.

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

PMID:
30352240
DOI:
10.1016/j.lfs.2018.10.034
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center