Apigenin induces apoptosis by targeting inhibitor of apoptosis proteins and Ku70–Bax interaction in prostate cancer

Abstract

Dysfunction of the apoptotic pathway in prostate cancer cells confers apoptosis resistance towards various therapies. A novel strategy to overcome resistance is to directly target the apoptotic pathway in cancer cells. Apigenin, an anticancer agent, selectively toxic to cancer cells induces cell cycle arrest and apoptosis through mechanisms which are not fully explored. In the present study we provide novel insight into the mechanisms of apoptosis induction by apigenin. Treatment of androgen-refractory human prostate cancer PC-3 and DU145 cells with apigenin resulted in dose-dependent suppression of XIAP, c-IAP1, c-IAP2 and survivin protein levels. Apigenin treatment resulted in significant decrease in cell viability and apoptosis induction with the increase of cytochrome C in time-dependent manner. These effects of apigenin were accompanied by decrease in Bcl-xL and Bcl-2 and increase in the active form of Bax protein. The apigenin-mediated increase in Bax was due to dissociation of Bax from Ku70 which is essential for apoptotic activity of Bax. Apigenin treatment resulted in the inhibition of class I histone deacetylases and HDAC1 protein expression, thereby increasing the acetylation of Ku70 and the dissociation of Bax resulting in apoptosis of cancer cells. Furthermore, apigenin significantly reduced HDAC1 occupancy at the XIAP promoter, suggesting that histone deacetylation might be critical for XIAP downregulation. These results suggest that apigenin targets inhibitor of apoptosis proteins and Ku70–Bax interaction in the induction of apoptosis in prostate cancer cells and in athymic nude mouse xenograft model endorsing its in vivo efficacy.

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Abbreviations

IAP:

Inhibitor of apoptosis protein

XIAP:

X-linked inhibitor of apoptosis

HDAC:

Histone deacetylases

NF-κB:

Nuclear factor kappa-B

IGF:

Insulin-like growth factor

PI3K:

Phosphoinositide 3-kinase

HIF:

Hypoxia-inducible factor

MAPK:

Mitogen-activated protein kinases

SAHA:

Suberoylanilide hydroxamic acid

TSA:

Trichostatin A

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Acknowledgments

This work was supported by grants from United States Public Health Services RO1CA108512, RO1AT002709 to SG and RO3CA1376676 to SS.

Conflict of interest

The authors have no competing interest.

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Correspondence to Sanjay Gupta.

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Shukla, S., Fu, P. & Gupta, S. Apigenin induces apoptosis by targeting inhibitor of apoptosis proteins and Ku70–Bax interaction in prostate cancer. Apoptosis 19, 883–894 (2014). https://doi.org/10.1007/s10495-014-0971-6

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Keywords

  • Prostate cancer
  • Apigenin
  • Inhibitor of apoptosis proteins
  • Apoptosis
  • Ku70
  • Histone deacetylase