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Chemotherapy induces ovarian cancer cell repopulation through the caspase 3-mediated arachidonic acid metabolic pathway

Authors Cui LZ, Zhao YW, Pan Y, Zheng X, Shao D, Jia Y, He K, Li K, Chen L

Received 31 August 2017

Accepted for publication 10 November 2017

Published 8 December 2017 Volume 2017:10 Pages 5817—5826


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Geoffrey Pietersz

Lianzhi Cui,1,2 Yawei Zhao,1 Yue Pan,1 Xiao Zheng,1 Dan Shao,1 Yong Jia,3 Kan He,1 Kun Li,3 Li Chen1,3

1Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, 2Clinical Laboratory, Jilin Cancer Hospital, Changchun, 3School of Nursing, Jilin University, Changchun, China

Abstract: Recurrence is one of the major causes of high mortality in ovarian cancer. However, the mechanism of ovarian cancer recurrence after chemotherapy has not been fully understood. In the present study, we investigated the effect of chemotherapy-induced tumor microenvironment on the proliferation of SKOV3 cells. We have shown that SKOV3 cells repopulated faster in the culture medium from apoptotic SKOV3 ovarian cancer cells after 24 h of etoposide phosphate (VP-16) treatment. We found that during apoptosis, cleaved caspase 3 could activate cytosolic calcium-independent phospholipase A2, which stimulated the release of arachidonic acid (AA) and triggered the production of prostaglandin E2 (PGE2). An increased level of phosphorylated focal adhesion kinase (FAK) subsequently facilitated the reproliferation of SKOV3 cells, and VP-16-induced repopulation effects were partially reversed by the FAK inhibitor PF562271. Furthermore, the plasma AA-to-PGE2 ratio and tumoral FAK expression of ovarian cancer patients after chemotherapy were significantly lower than those before chemotherapy. Taken together, our results indicate that chemotherapy-induced apoptotic cancer cells can produce PGE2-enriched microenvironment through caspase 3-mediated AA metabolic pathway, which could lead to the abnormal activation of FAK and eventually accelerate the repopulation of SKOV3 cells. Our study provides novel insight into a mechanism that may be utilized to prevent ovarian cancer recurrence in response to chemotherapy.

Keywords: ovarian cancer, repopulation, chemotherapy, apoptosis, FAK

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