Oncotarget

Research Papers:

Mitochondrial ROS activates ERK/autophagy pathway as a protected mechanism against deoxypodophyllotoxin-induced apoptosis

Sang-Hun Kim, Kwang-Youn Kim, Sul-Gi Park, Sun-Nyoung Yu, Young-Wook Kim, Hyo-Won Nam, Hyun-Hee An, Young-Woo Kim and Soon-Cheol Ahn _

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Oncotarget. 2017; 8:111581-111596. https://doi.org/10.18632/oncotarget.22875

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Abstract

Sang-Hun Kim1,2, Kwang-Youn Kim3, Sul-Gi Park1, Sun-Nyoung Yu1, Young-Wook Kim1, Hyo-Won Nam1, Hyun-Hee An1, Young-Woo Kim4 and Soon-Cheol Ahn1,5

1Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea

2Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA

3Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea

4Department of Herbal Formula, Medical Research Center (MRC-GHF), College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea

5Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan National University, Yangsan 50612, Republic of Korea

Correspondence to:

Soon-Cheol Ahn, email: ahnsc@pusan.ac.kr

Keywords: Deoxypodophyllotoxin; apoptosis; autophagy; mitochondrial ROS; ERK

Received: July 11, 2017     Accepted: October 28, 2017     Published: December 04, 2017

ABSTRACT

Deoxypodophyllotoxin (DPT) is a naturally occurring flavolignan isolated from Anthriscus sylvestris. Recently, it has been reported that DPT inhibits tubulin polymerization and induces G2/M cell cycle arrest followed by apoptosis through multiple cellular processes. Despite these findings, details regarding the cellular and molecular mechanisms underlying the DPT-mediated cell death have been poorly understood. To define a mechanism of DPT-mediated cell death response, we examined whether DPT activates signaling pathways for autophagy and apoptosis. We demonstrated that DPT inhibited cell viability and induced apoptosis in prostate cancer cell lines, as evidenced by a mitochondrial membrane potential and expression of apoptosis-related proteins. Reactive oxygen species (ROS), primarily generated from the mitochondria, play an important role in various cellular responses, such as apoptosis and autophagy. DPT significantly triggered mitochondrial ROS, which were detected by MitoSOX, a selective fluorescent dye of mitochondria-derived ROS. Furthermore, DPT induced autophagy through an up-regulation of autophagic biomarkers, including a conversion of microtubule-associated protein 1 light chain 3 - I (LC3-I) into LC3-II and a formation of acidic vesicular organelles. Moreover, mitochondrial ROS promoted AKT-independent autophagy and ERK signaling. The inhibition of autophagy with 3-methyladenine or LC3 knockdown enhanced DPT-induced apoptosis, suggesting that an autophagy plays a protective role in cell survival against apoptotic prostate cancer cells. Additionally, the results from an in vivo xenograft model confirmed that DPT inhibited tumor growth by regulating the apoptosis- and autophagy-related proteins.


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