Isolinderalactone Induces Cell Death via Mitochondrial Superoxide- and STAT3-Mediated Pathways in Human Ovarian Cancer Cells.

Shakya Rajina,Joon-Seok Choi,Sang Hoon Joo,Woo Jean Kim,Hwa Kyoung Shin,Jung-Hyun Shim,Kyung-Soo Chun,Seo-Yeon Lee

doi:10.3390/ijms21207530

Abstract

The mortality rate of ovarian cancer (OC) worldwide increases with age. OC is an often fatal cancer with a curative rate of only 20–30%, as symptoms often appear after disease progression. Studies have reported that isolinderalactone (ILL), a furanosesquiterpene derivative extracted from the dried root of Lindera aggregata, can inhibit several cancer cell lines’ growth. However, the molecular mechanisms underlying ILL activities in human OC cells remain unexplored. This study investigated the antitumor activities of ILL in human OC cells by inducing mitochondrial superoxide (mtSO) and JAK-signal transducer and activator of transcription 3 (STAT3)-dependent cell death. ILL caused cell death in SKOV-3 and OVCAR-3 cells and increased the cell proportion in the subG1 phase. Additionally, ILL significantly induced mtSO production and reduced ROS production. Moreover, ILL downregulated mitochondrial membrane potential and the expression levels of anti-apoptotic Bcl-2 family proteins and superoxide dismutase (SOD)2. Results showed that ILL decreased phosphorylation of serine 727 and tyrosine 705 of STAT3 and expression of survivin, a STAT3-regulated gene. Furthermore, ILL-induced cell death was reversed by pretreatment of Mito-TEMPO, a mitochondria-specific antioxidant. These results suggest that ILL induces cell death by upregulation of mtSO, downregulation of mitochondrial SOD2, and inactivation of the STAT3-mediated pathway.

Highlights

Ovarian cancer (OC) is a group of diseases originating in the ovaries, fallopian tubes, and peritoneum that are classified as epithelial cell carcinomas, germ cell tumors, and astrocyte stromal tumors, depending on the tissue of origin [1]
The study results suggest that ILL induced apoptosis in human ovarian cancer (OC) cells by increasing production of mitochondrial superoxide, decreasing the expression of SOD2, and interfering with the signal transducer and activator of transcription 3 (STAT3)-mediated signaling pathway
To assess the mechanism underlying ILL-induced apoptosis, we examined the expression and phosphorylation levels of signaling molecules involved in the JAK/STAT signaling axis

Summary

Introduction

Ovarian cancer (OC) is a group of diseases originating in the ovaries, fallopian tubes, and peritoneum that are classified as epithelial cell carcinomas, germ cell tumors, and astrocyte stromal tumors, depending on the tissue of origin [1]. The main constituents of Lindera extract include the sesquiterpene compounds linderane, linderalactone, and isolinderalactone (ILL), which are reported to convey anti-cancer effects [20,21,22]. Among these three furanosesquiterpene derivatives, ILL was reported to exhibit greater cell death-inducing activity in human non-small lung cancer A549 cells by increasing the expression level of p21, which induces cell cycle arrest and participates in the regulation of the Fas/Fas ligand-mediated apoptosis pathway [20]. The study results suggest that ILL induced apoptosis in human OC cells by increasing production of mitochondrial superoxide (mtSO), decreasing the expression of SOD2, and interfering with the STAT3-mediated signaling pathway

Results

Cell Viability Assay

Immunoblot Analysis

Statistical Analysis