2. Academic Validation
  3. Deoxypodophyllotoxin induces cytoprotective autophagy against apoptosis via inhibition of PI3K/AKT/mTOR pathway in osteosarcoma U2OS cells

Deoxypodophyllotoxin induces cytoprotective autophagy against apoptosis via inhibition of PI3K/AKT/mTOR pathway in osteosarcoma U2OS cells

  • Pharmacol Rep. 2017 Oct;69(5):878-884. doi: 10.1016/j.pharep.2017.04.007.
Sang-Hun Kim 1,  Kyo-Min Son 2,  Kwang-Youn Kim 3,  Sun-Nyoung Yu 1,  Sul-Gi Park 1,  Young-Wook Kim 1,  Hyo-Won Nam 1,  Jeung-Tak Suh 4,  Jae-Hoon Ji 5,  Soon-Cheol Ahn 6
Affiliations

Affiliations

  • 1 Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
  • 2 Department of Orthopedic Surgery, Hana Hospital, Changwon, Republic of Korea.
  • 3 Department of Herbal Formula, Medical Research Center (MRC-GHF), College of Oriental Medicine, Daegu Haany University, Gyeongsan, Republic of Korea.
  • 4 Department of Orthopedic Surgery, Pusan National University School of Medicine, Busan, Republic of Korea.
  • 5 Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Republic of Korea. Electronic address: jij@ajou.ac.kr.
  • 6 Department of Microbiology & Immunology, Pusan National University School of Medicine, Yangsan, Republic of Korea; Immunoregulatory Therapeutics Group in Brain Busan 21 Project, Pusan National University, Yangsan, Republic of Korea. Electronic address: ahnsc@pusan.ac.kr.
PMID: 28623712 DOI: 10.1016/j.pharep.2017.04.007
Abstract

Background: A natural compound deoxypodophyllotoxin (DPT) possesses potent anti-proliferative and anti-tumor properties on several Cancer types. It triggers cell cycle arrest followed by Apoptosis through various cellular processes. However, it is limited to the action mechanism of DPT-mediated cell death modes via Apoptosis and Autophagy.

Methods: Cell viability assay, morphological changes, annexin-V/propidium iodide (PI) assay, Reactive Oxygen Species (ROS), acridine orange staining, and Western blot analyses were evaluated.

Results: We demonstrated that DPT induced both Apoptosis and Autophagy via production of mitochondrial Reactive Oxygen Species (ROS). DPT suppressed the PI3K/Akt/mTOR signaling cascades to lead Autophagy process, resulting from conversion of LIGHT chain 3-I (LC3-I) into LC3-II and acidic vesicular organelles (AVOs) formation. Even if DPT-induced ROS were occurred in both Apoptosis and Autophagy, inhibition of ROS generation enhanced cell viability. Otherwise, 3-methyladeine (3-MA) impeding on Autophagy accelerated an apoptotic response caused by DPT. Therefore, these findings suggest that DPT triggers cytoprotective Autophagy against cytotoxic Apoptosis.

Conclusion: Autophagy is required for cell survival by inhibition of Apoptosis through down-regulation of PI3K/Akt/mTOR pathway against DPT-induced Apoptosis in U2OS cells.

Keywords

Apoptosis; DPT; Deoxypodophyllotoxin; ROS; Reactive oxygen species.

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