Open Access

Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer

  • Authors:
    • Namrata Khurana
    • Hogyoung Kim
    • Partha K. Chandra
    • Sudha Talwar
    • Pankaj Sharma
    • Asim B. Abdel-Mageed
    • Suresh C. Sikka
    • Debasis Mondal
  • View Affiliations

  • Published online on: August 30, 2017     https://doi.org/10.3892/or.2017.5932
  • Pages: 2774-2786
  • Copyright: © Khurana et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Prostate cancer (PCa) cells expressing full-length androgen receptor (AR-FL) are susceptible to androgen deprivation therapy (ADT). However, outgrowth of castration-resistant prostate cancer (CRPC) can occur due to the expression of constitutively active (ligand-independent) AR splice variants, particularly AR-V7. We previously demonstrated that sulforaphane (SFN), an isothiocyanate phytochemical, can decrease AR-FL levels in the PCa cell lines, LNCaP and C4-2B. Here, we examined the efficacy of SFN in targeting both AR-FL and AR-V7 in the CRPC cell line, CWR22Rv1 (22Rv1). MTT cell viability, wound-heal assay, and colony forming unit (CFU) measurements revealed that 22Rv1 cells are resistant to the anti-androgen, enzalutamide (ENZ). However, co-exposure to SFN sensitized these cells to the potent anticancer effects of ENZ (P<0.05). Immunoblot analyses showed that SFN (5-20 µM) rapidly decreases both AR-FL and AR-V7 levels, and immunofluorescence microscopy (IFM) depicted decreased AR in both cytoplasm and nucleus with SFN treatment. SFN increased both ubiquitination and proteasomal activity in 22Rv1 cells. Studies using a protein synthesis inhibitor (cycloheximide) or a proteasomal inhibitor (MG132) indicated that SFN increases both ubiquitin-mediated aggregation and subsequent proteasomal-degradation of AR proteins. Previous studies reported that SFN inhibits the chaperone activity of heat-shock protein 90 (Hsp90) and induces the nuclear factor erythroid-2-like 2 (Nrf2) transcription factor. Therefore, we investigated whether the Hsp90 inhibitor, ganetespib (G) or the Nrf2 activator, bardoxolone methyl (BM) can similarly suppress AR levels in 22Rv1 cells. Low doses of G and BM, alone or in combination, decreased both AR-FL and AR-V7 levels, and combined exposure to G+BM sensitized 22Rv1 cells to ENZ. Therefore, adjunct treatment with the phytochemical SFN or a safe pharmaceutical combination of G+BM may be effective against CRPC cells, especially those expressing AR-V7.
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November-2017
Volume 38 Issue 5

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Online ISSN:1791-2431

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Spandidos Publications style
Khurana N, Kim H, Chandra PK, Talwar S, Sharma P, Abdel-Mageed AB, Sikka SC and Mondal D: Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer. Oncol Rep 38: 2774-2786, 2017
APA
Khurana, N., Kim, H., Chandra, P.K., Talwar, S., Sharma, P., Abdel-Mageed, A.B. ... Mondal, D. (2017). Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer. Oncology Reports, 38, 2774-2786. https://doi.org/10.3892/or.2017.5932
MLA
Khurana, N., Kim, H., Chandra, P. K., Talwar, S., Sharma, P., Abdel-Mageed, A. B., Sikka, S. C., Mondal, D."Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer". Oncology Reports 38.5 (2017): 2774-2786.
Chicago
Khurana, N., Kim, H., Chandra, P. K., Talwar, S., Sharma, P., Abdel-Mageed, A. B., Sikka, S. C., Mondal, D."Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer". Oncology Reports 38, no. 5 (2017): 2774-2786. https://doi.org/10.3892/or.2017.5932