The pro-apoptotic actions of 2-methoxyestradiol against ovarian cancer involve catalytic activation of PKCδ signaling.

Purab Pal,Karen Hales,Dale Buchanan Hales

doi:10.18632/oncotarget.27760

Abstract

Background: 2-methoxyestradiol (2MeOE2) is a natural metabolite of estradiol, which is generated by the action of CYP1A1 enzyme in the liver. We have previously shown that a flaxseed-supplemented diet decreases both the incidence and severity of ovarian cancer in laying hens, also induces CYP1A1 expression in liver. Recently, we have shown that as a biologically derived active component of flax diet, 2MeOE2 induces apoptosis in ovarian cancer cells which is partially dependent on p38 MAPK. The objective of this study was to elucidate the molecular mechanism of actions of 2MeOE2, a known microtubule disrupting agent, in inducing apoptosis in ovarian tumors.Results: 2MeOE2 induces γH2Ax expression and apoptotic histone modifications in ovarian cancer cells, which are predicted downstream targets of protein kinase Cδ (PKCδ) during apoptosis. Overexpressing full length PKCδ alone does not induce apoptosis but potentiates 2MeOE2-mediated apoptosis. C3-domain mutated dominant-negative PKCδ (PKCδDN) significantly reduces 2MeOE2-induced caspase-3 cleavage and apoptotic histone modification. Silencing PKCδ diminishes 2MeOE2-mediated apoptosis. The catalytic fragment of PKCδ (PKCδCAT) evokes pro-apoptotic effects which are principally dependent on p38 MAPK phosphorylation.Conclusions: The pro-apoptotic actions of 2MeOE2 are in part dependent on catalytic activation of PKCδ. Catalytic activation of PKCδ accelerates the 2MeOE2-induced apoptotic cascade. This study describes a novel molecular action of flaxseed diet in ovarian cancer.

Highlights

With an estimated 22,530 cases reported and 13,980 estimated deaths in the year 2019, ovarian cancer is the deadliest gynecological disease accounting for more deaths than any other cancer in the female reproductive tract
The catalytic fragment of protein kinase Cδ (PKCδ) (PKCδCAT) evokes pro-apoptotic effects which are principally dependent on p38 Mitogen-activated protein kinase (MAPK) phosphorylation
This study describes a novel molecular action of flaxseed diet in ovarian cancer

Summary

Introduction

With an estimated 22,530 cases reported and 13,980 estimated deaths in the year 2019, ovarian cancer is the deadliest gynecological disease accounting for more deaths than any other cancer in the female reproductive tract. The disease is often diagnosed at an advanced stage, which contributes to a low five-year survival rate of only 47.6% in the United States [1]. Our laboratory studies epithelial ovarian cancer (EOC) in laying hens, the only known natural animal model that spontaneously develops the disease over its lifespan. The disease in hens is very similar to the human form in expression of similar molecular markers such as CA-125 and e-cadherin, and symptoms such as accumulation of ascitic fluid and peritoneal metastasis in the advanced stage. Onset of EOC in laying hens is positively correlated with the number of lifetime ovulation. Suppressing ovulation reduces ovarian cancer incidence in laying hens, similar to the preventative effects of reduced ovulation observed in women

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