Oncotarget

Research Papers:

Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells

Sham S. Kakar _, Seema Parte, Kelsey Carter, Irving G. Joshua, Christopher Worth, Pranela Rameshwar and Mariusz Z. Ratajczak

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Oncotarget. 2017; 8:74494-74505. https://doi.org/10.18632/oncotarget.20170

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Abstract

Sham S. Kakar1,2, Seema Parte2, Kelsey Carter1, Irving G. Joshua1, Christopher Worth2, Pranela Rameshwar3 and Mariusz Z. Ratajczak4

1Department of Physiology, University of Louisville, Louisville, KY 40202, USA

2James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA

3Department of Medicine, Hematology/Oncology, Rutgers, New Jersey Medical School, Newark, NJ 07103, USA

4Department of Medicine, University of Louisville, Louisville, KY 40202, USA

Correspondence to:

Sham S. Kakar, email: sskaka01@louisville.edu

Keywords: cancer stem cells, ALDH1, ovarian cancer, withaferin A, securin

Received: May 09, 2017    Accepted: June 26, 2017    Published: August 10, 2017

ABSTRACT

Ovarian cancer is the fifth leading cause of deaths due to cancer among women in the United States. In 2017, 22,440 women are expected to be diagnosed with ovarian cancer and 14,080 women will die with it. Currently used chemotherapies (Cisplatin or platinum/taxane combination) targets cancer cells, but spares cancer stem cells (CSCs), which are responsible for tumor relapse leading to recurrence of cancer. Aldehyde dehydrogenase I (ALDH1) positive cancer stem cells are one of the major populations in ovarian tumor and have been related to tumor progression and metastasis. In our studies, we observed expression of ALDH1 in both ovarian surface epithelium (OSE) and cortex with high levels of expression in OSE in normal ovary and benign (BN) tumor, compared to borderline (BL) and high grade (HG) ovarian tumors. In contrast, high levels of expression of ALDH1 were observed in cortex in BL and HG tumors compared to normal ovary and BN tumor. Withaferin A (WFA) alone or in combination with cisplatin (CIS) significantly inhibited the spheroid formation (tumorigenic potential) of isolated ALDH1 CSCs in vitro and significantly reduced its expression in tumors collected from mice bearing orthotopic ovarian tumor compared to control. Treatment of animals with CIS alone significantly increased the ALDH1 CSC population in tumors, suggesting that CIS targets cancer cells but spares cancer stem cells, which undergo amplification. WFA and CIS combination suppresses the expression of securin an “oncogene”, suggesting that securin may serve as a downstream signaling gene to mediate the antitumor effects of WFA.


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