Oleocanthal Attenuates Metastatic Castration-Resistant Prostate Cancer Progression and Recurrence by Targeting SMYD2

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is the most aggressive prostate cancer (PC) phenotype. Cellular lysine methylation is driven by protein lysine methyltransferases (PKMTs), such as those in the SET- and MYND-containing protein (SMYD) family, including SMYD2 methylate, and several histone and non-histone proteins. SMYD2 is dysregulated in metastatic PC patients with high Gleason score and shorter survival. The Mediterranean, extra-virgin-olive-oil-rich diet ingredient S-(-)-oleocanthal (OC) inhibited SMYD2 in biochemical assays and suppressed viability, migration, invasion, and colony formation of PC-3, CWR-R1ca, PC-3M, and DU-145 PC cell lines with IC50 range from high nM to low µM. OC’s in vitro antiproliferative effect was comparable to standard anti-PC chemotherapies or hormone therapies. A daily, oral 10 mg/kg dose of OC for 11 days effectively suppressed the progression of the mCRPC CWR-R1ca cells engrafted into male nude mice. Daily, oral OC treatment for 30 days suppressed tumor locoregional and distant recurrences after the primary tumors’ surgical excision. Collected OC-treated animal tumors showed marked SMYD2 reduction. OC-treated mice showed significant serum PSA reduction. For the first time, this study showed SMYD2 as novel molecular target in mCRPC, and OC emerged as a specific SMYD2 lead inhibitor. OC prevailed over previously reported SMYD2 inhibitors, with validated in vivo potency and high safety profile, and, therefore, is proposed as a novel nutraceutical for mCRPC progression and recurrence control.

An Appraisal of the Oleocanthal-Rich Extra Virgin Olive Oil (EVOO) and Its Potential Anticancer and Neuroprotective Properties

“…Moreover, a significant 15.9% reduction in the serum levels of the prostate cancer recurrence marker PSA (Prostate-specific antigen) was observed in the oleocanthal-treated mice, as compared to the placebo control-treated group. Thus, this study suggested SMYD2 as a novel molecular target in mCRPC and oleocanthal as a specific SMYD2 inhibitor [45].…”

“…Siddique et al [45] also demonstrated that a daily oral oleocanthal dose of 10 mg/kg for 11 days effectively suppressed the progression of the metastatic castration-resistant prostate cancer (mCRPC) CWR-R1ca cells engrafted into orthotopic athymic nude mice. Authors did not observe gross adverse and/or behavioral responses in male athymic nude mice treated with oleocanthal, and the mice's mean body weight was not significantly different over the experiment course in placebo control-and oleocanthal-treated groups.…”

Targeting Epigenetic Changes Mediated by Members of the SMYD Family of Lysine Methyltransferases

“…An ingredient in extra-virgin olive oil, S-(-)-oleocanthal, emerged as a specific SMYD2 lead inhibitor. This compound had high in vivo potency and a strong safety profile and has been proposed as a novel nutraceutical to treat metastatic castration-resistant prostate cancer [ 110 ].…”

Oleocanthal, an Antioxidant Phenolic Compound in Extra Virgin Olive Oil (EVOO): A Comprehensive Systematic Review of Its Potential in Inflammation and Cancer

“…For this reason, the investigation of treatments for cancers like metastatic castration-resistant prostate cancer (mCRPC), one of the most aggressive prostate cancer (PC) phenotypes, is important. A breakthrough was made when it was found that OC exhibits inhibitory characteristics related to SMYD2 (an enzyme involved in the methylation of protein lysines) and demonstrates positive effects on mCRPC cells [46].…”

“…OC reduces the proliferation of TNBC cells [12] EVOO extract enriched with OC reduces cell proliferation and augments cell death [13] OC-(+)-xylitol solid dispersion formulation enhances antitumoral c-Met activity [14] Inhibits cell migration, proliferation, and migration in the metastatic MCF7 and MDA-MB-231 breast cancer cells [34] Prevents the recurrence of localized and regional breast cancer [35] OC + Tamoxifen: Potentially enhances tamoxifen's effectiveness in inhibiting the growth of cells ↓Expression of ERα [48] OC + Lapatinib: Inhibits EGFR, HER-2, and c-Met receptors [49] Inhibition of TRPC6, cell proliferation, and cell migration [50] Prostate cancer Inhibits cell migration, proliferation, and migration in PC-3 prostate cancer cells [34] ↓PSA levels in mouse model [46] Lung cancer Inhibits c-Met-COX2 [38] Liver cancer Inhibits activation of STAT3 [42] Inhibits proliferation of human liver cancer cells [13] Inhibits cell colonies, triggers apoptosis, generation of ROS species [47] Colon cancer Generation of ROS species, apoptosis, inhibition of cell colonies [47] Colorectal adenocarcinoma Controls the growth and apoptosis of cancer cells in HT-29 cells through AMPK activation and COX-2 expression [55] Gastric adenocarcinoma Enriched OC oil stimulates reactive oxygen species (ROS) and the activation of the tumor suppressor protein p53 [51] Neuroblastoma Inhibition of cell proliferation of neuroblastoma cancer cells [56] Melanoma Inhibition of STAT3 signaling pathway [41] OC induces cytotoxicity against human melanoma ↓ERK1/2 and AKT phosphorylation ↓Bcl-2 expression [43] Hematopoietic tumor cells AML cells: cell death through caspase activation [53] ALL cells: cell death independent of caspase pathway [53] AML…”