The p53 mutation-site in prostate cancer determines its sensitivity to phenethyl isothiocyanate induced growth inhibition

Authors: AGGARWAL, MONICA - Georgetown University; SAXENA, RAHUL - Georgetown University; ASIF, NASIR - Georgetown University; SINCLAIR, ELIZABETH - Georgetown University; TAN, JUDY - Georgetown University; CRUZ, IDALIA - Georgetown University; BERRY, DEBORAH - Georgetown University; KALLAKURY, BHASKAR - Georgetown University; Pham, Quynhchi; Wang, Thomas - Tom; FUNG-LUNG, CHUNG - Georgetown University

Submitted to: Journal of Experimental and Clinical Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/4/2019
Publication Date: 7/15/2019
Citation: Aggarwal, M., Saxena, R., Asif, N., Sinclair, E., Tan, J., Cruz, I., Berry, D., Kallakury, B., Pham, Q., Wang, T.T., Fung-Lung, C. 2019. The p53 mutation-site in prostate cancer determines its sensitivity to phenethyl isothiocyanate induced growth inhibition. Journal of Experimental and Clinical Cancer Research. 38(1):307. https://doi.org/10.1186/s13046-019-1267-z.
DOI: https://doi.org/10.1186/s13046-019-1267-z

Interpretive Summary: Cruciferous vegetable-derived compounds may be protective against the development of cancer but the mechanisms remain unclear. We reported previously that phenethyl isothiocyanate (PEITC), a dietary-related compound, can reactivate p53 mutant in vitro and in SK-BR-3 (p53R175H) breast xenograft model resulting in tumor inhibition. Because of the diversity of human cancers with p53 mutations, these findings raise important questions whether this mechanism operates in different cancer types with the same or different p53 mutations. In this study, we demonstrated that PEITC inhibits the growth of prostate cancer cells with different p53 mutations, however, to differential extents, and cells harboring p53R175H mutant are most sensitive. These results show that PEITC’s anti-cancer activity is p53 mutation-site dependent. We showed that PEITC inhibited the growth of DU145 cells that co-express p53P223L and p53V274F and PEITC targets p53P223L mutant by selectively restoring transactivation functions only to p53P223L mutant, but not p53V274F. These results suggest that the restoration of mutant p53 by PEITC is mutant type-dependent. The restored WT p53 induces apoptosis by activating canonical p53 targets, delaying cells in G1 phase and phosphorylating ATM. PEITC induced p53-pathway activation is p73 independent. Importantly, PEITC reactivated p53 mutant in DU145 prostate xenograft model, resulting in significant tumor inhibition. Further, PEITC inhibits proliferation and induces apoptosis in prostate cancer cells expressing different “hotspot” p53 mutants, p53R248W and p53R175H, with differential potency via restoration of WT p53 functions. These studies provide the first evidence that PEITC mediated growth inhibition of prostate cancer cells is p53 mutation-site dependent. This study provides information about health-promoting effects of plant-derived compounds and their mechanism on cancer prevention. The work provides information that can benefit basic, as well as translation scientists who work on diet and cancer prevention.

Technical Abstract: We reported previously that phenethyl isothiocyanate (PEITC), a dietary-related compound, can reactivate p53 mutant in vitro and in SK-BR-3 (p53R175H) breast xenograft models resulting in tumor inhibition. Because of the diversity of human cancers with p53 mutations, these findings raise important questions whether this mechanism operates in different cancer types with the same or different p53 mutations. In this study, we demonstrated that PEITC inhibits the growth of prostate cancer cells with different p53 mutations, however, to differential extents, and cells harboring p53R175H mutant are most sensitive. These results show that PEITC’s anti-cancer activity is p53 mutation-site dependent. We showed that PEITC inhibited the growth of DU145 cells that co-express p53P223L and p53V274F and PEITC targets p53P223L mutant by selectively restoring transactivation functions only to p53P223L mutant, but not p53V274F. These results suggest that the restoration of mutant p53 by PEITC is mutant type-dependent. The restored WT p53 induces apoptosis by activating canonical p53 targets, delaying cells in G1 phase and phosphorylating ATM. PEITC induced p53-pathway activation is p73 independent. Importantly, PEITC reactivated the p53 mutant in the DU145 prostate xenograft model, resulting in significant tumor inhibition. Further, PEITC inhibits proliferation and induces apoptosis in prostate cancer cells expressing different “hotspot” p53 mutants, p53R248W and p53R175H, with differential potency via the restoration of WT p53 functions. These studies provide the first evidence that PEITC mediated growth inhibition of prostate cancer cells is p53 mutation-site dependent.