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Apigenin manipulates the ubiquitin–proteasome system to rescue estrogen receptor-β from degradation and induce apoptosis in prostate cancer cells

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European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

To investigate apigenin (5,7,4-trihydroxyflavone), a dietary flavonoid with proteasome-inhibitory activity (desired for the management of multiple types of cancers), against FDA-approved anticancer proteasome inhibitor bortezomib in context to its effects on the tumor suppressor estrogen receptor-beta (ER-β) in prostate cancer cells.

Methods

Prostate cancer (PC-3) cells were treated with either apigenin or bortezomib, and proliferation inhibition was correlated with proteasomal biochemistry, ER-degradation and cell apoptosis.

Results

Apigenin specifically inhibited only chymotrypsin-like activity of proteasome without affecting trypsin and caspase-like activities, which was in contrast to the non-specific inhibition of all the three activities by bortezomib. Apigenin selectively increased the protein levels of ER-β at 1.8 and 10.0 µM (without affecting mRNA levels) and preferentially accumulated ubiquitinated ER-β over ER-α in PC-3. Apigenin-treated cells exhibited increased ER-β interactions with ubiquitin-protein ligase E6AP, downregulated PSMA5 (α-5 subunit for assembly of 20S proteasome) without affecting PSMB1 (β-1 subunit), PSMB2 (β-2 subunit) and PSMB5 (β-5 subunit, whose overexpression by bortezomib causes drug resistance) of proteasome at mRNA levels. Caspase-3 activation in PC-3 by apigenin was dependent on caspase-8 activity but independent of mitochondrial membrane depolarization. The deubiquitinase USP14 activity, which antagonizes degradation of proteins via proteasome, was significantly increased by apigenin treatment.

Conclusions

Apigenin selectively inhibits proteasomal degradation of tumor suppressor ER-β by specifically inhibiting chymotrypsin-like activity of proteasome, preventing its assembly via PSMA5 and inhibiting USP14 enzyme activity in prostate cancer cells, resulting in cancer cell apoptosis. Unlike bortezomib, apigenin’s actions are subtle, precise, mechanistically distinct and capable of abstaining drug resistance.

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Acknowledgments

This study was supported by a grant from the Ministry of Health and Family Welfare, Government of India (GAP0001). [CDRI communication number 8844]

Conflict of interest

None.

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Authors and Affiliations

  1. Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Vishal Singh, Vikas Sharma, Vikas Verma, Deepti Pandey, Santosh K. Yadav, Jagdamba P. Maikhuri & Gopal Gupta

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  1. Vishal Singh
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  2. Vikas Sharma
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  3. Vikas Verma
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  7. Gopal Gupta
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Correspondence to Gopal Gupta.

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Singh, V., Sharma, V., Verma, V. et al. Apigenin manipulates the ubiquitin–proteasome system to rescue estrogen receptor-β from degradation and induce apoptosis in prostate cancer cells. Eur J Nutr 54, 1255–1267 (2015). https://doi.org/10.1007/s00394-014-0803-z

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  • DOI: https://doi.org/10.1007/s00394-014-0803-z

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