Research Papers:

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

Purab Pal, Karen Hales and Dale Buchanan Hales _

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Oncotarget. 2020; 11:3646-3659. https://doi.org/10.18632/oncotarget.27760

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Purab Pal1, Karen Hales2 and Dale Buchanan Hales1,2

1 Department of Physiology, Southern Illinois University, Carbondale, IL 62901, USA

2 Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA

Correspondence to:

Dale Buchanan Hales,email: [email protected]

Keywords: 2-methoxyestradiol; ovarian cancer; protein kinase Cδ; p38 MAPK; apoptosis

Received: July 09, 2020     Accepted: September 10, 2020     Published: October 06, 2020

Copyright: © 2020 Pal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.

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