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BioMed Research International
Volume 2015, Article ID 738241, 13 pages
http://dx.doi.org/10.1155/2015/738241
Research Article

Heteronemin, a Spongean Sesterterpene, Induces Cell Apoptosis and Autophagy in Human Renal Carcinoma Cells

1Pharmacological Institute, College of Medicine, National Taiwan University, No. 1 Jen-Ai Road, Section 1, Taipei 10051, Taiwan
2Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 944, Taiwan
3National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan
4The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 11031, Taiwan
5Department of Pharmacology, College of Medicine, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110311, Taiwan

Received 23 July 2014; Accepted 26 August 2014

Academic Editor: Chin-Chung Wu

Copyright © 2015 Szu-Ying Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Heteronemin is a bioactive marine sesterterpene isolated from the sponge Hyrtios sp. Previous reports have shown that heteronemin possesses anticancer activity. Here, heteronemin displayed cytotoxic effects against three human cancer cell lines (A549, ACHN, and A498) and exhibited potent activity in A498 human renal carcinoma cells, with an IC50 value of 1.57 μM by MTT assay and a GI50 value of 0.77 μM by SRB assay. Heteronemin initiates apoptotic cell death by downregulating Bcl-2 and Bcl-xL and upregulating Bax, leading to the disruption of the mitochondrial membrane potential and the release of cytochrome from the mitochondria. These effects were associated with the activation of caspase-3/caspase-8/caspase-9, followed by PARP cleavage. Furthermore, heteronemin inhibited the phosphorylation of AKT signaling pathway and ERK and activated p38 and JNK. The specific inhibition of the p38 pathway by SB203580 or p38 siRNA treatment reversed the heteronemin-induced cytotoxicity and apoptotic signaling. Heteronemin also induced autophagy in A498 cells, and treatment with chloroquine (autophagy inhibitor) or SP600125 (JNK inhibitor) inhibited autophagy and increased heteronemin-induced cytotoxicity and apoptotic signaling. Taken together, this study proposes a novel treatment paradigm in which the combination of heteronemin and autophagy inhibitors leads to enhanced RCC cell apoptosis.