Oncotarget: The pro-apoptotic actions of 2-methoxyestradiol against ovarian cancer

Oncotarget published "The pro-apoptotic actions of 2-methoxyestradiol against ovarian cancer involve catalytic activation of PKCδ signaling" which reported that the authors 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, they 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 Oncotarget study was to elucidate the molecular mechanism of actions of 2MeOE2, a known microtubule disrupting agent, in inducing apoptosis in ovarian tumors.

The objective of this Oncotarget study was to elucidate the molecular mechanism of actions of 2MeOE2, a known microtubule disrupting agent, in inducing apoptosis in ovarian tumors

2MeOE2 induces γH2Ax expression and apoptotic histone modifications in ovarian cancer cells, which are predicted downstream targets of protein kinase Cδ during apoptosis.

Overexpressing full length PKCδ alone does not induce apoptosis but potentiates 2MeOE2-mediated apoptosis.

Dr. Dale Buchanan Hales from The Southern Illinois University said, "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."

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.

Figure 7: Schematic diagram of the molecular action of 2MeOE₂. 2MeOE₂ -mediated pro-apoptotic actions involve the catalytic activation of PKCδ by cellular caspases. The catalytic fragment of PKCδ is responsible for the apoptotic histone modifications in the nucleus and activates p38 MAPK pathway in the cytosol, which induces more activation of caspases that consequently cleave and activate more PKCδ. Therefore this cycle accelerates and amplifies the 2MeOE₂-mediated apoptotic signal.

Their laboratory studies epithelial ovarian cancer in laying hens, the only known natural animal model that spontaneously develops the disease over its lifespan.

The research has shown that dietary ingestion of flaxseed reduces the onset and severity of ovarian cancer in laying hens.

Recently they have shown that 2MeOE2 induces apoptosis in human ovarian cancer cells.

The objective of this study was to investigate the epigenetic modifications exerted by 2MeOE2 and assess the role of PKCδ in 2MeOE2 actions in order to gain an in-depth mechanistic understanding of its molecular and cellular pro-apoptotic actions.

The Hales Research Team concluded in their Oncotarget Research Paper, "Our findings indicate that 2MeOE2 -mediated anti-tumor actions involve the catalytic activation of PKCδ in the pro-apoptotic pathway. The catalytic fragment of PKCδ is responsible for the apoptotic histone modifications and acceleration of the apoptotic cascade through p38 MAPK pathway. Dietary flaxseed supplementation activates PKCδ secondary to increasing endogenous production of 2MeOE2 which drives apoptosis in ovarian cancer cells (Figure 7). This study offers new insight into the molecular underpinnings of dietary flaxseed's chemopreventative actions in ovarian cancer."

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DOI - https://doi.org/10.18632/oncotarget.27760

Full text - https://www.oncotarget.com/article/27760/text/

Correspondence to - Dale Buchanan Hales - dhales@siumed.edu

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

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