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Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma

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Abstract

AMP-activated protein kinase (AMPK) performs a pivotal function in energy homeostasis via the monitoring of intracellular energy status. Once activated under the various metabolic stress conditions, AMPK regulates a multitude of metabolic pathways to balance cellular energy. In addition, AMPK also induces cell cycle arrest or apoptosis through several tumor suppressors including LKB1, TSC2, and p53. LKB1 is a direct upstream kinase of AMPK, while TSC2 and p53 are direct substrates of AMPK. Therefore, it is expected that activators of AMPK signal pathway might be useful for treatment or prevention of cancer. In the present study, we report that cryptotanshinone, a natural compound isolated from Salvia miltiorrhiza, robustly activated AMPK signaling pathway, including LKB1, p53, TSC2, thereby leading to suppression of mTORC1 in a number of LKB1-expressing cancer cells including HepG2 human hepatoma, but not in LKB1-deficient cancer cells. Cryptotanshinone induced HepG2 cell cycle arrest at the G1 phase in an AMPK-dependent manner, and a portion of cells underwent apoptosis as a result of long-term treatment. It also induced autophagic HepG2 cell death in an AMPK-dependent manner. Cryptotanshinone significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model, with a substantial activation of AMPK signal pathways. Collectively, we demonstrate for the first time that cryptotanshinone harbors the therapeutic potential for the treatment of cancer through AMPK activation.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 20120009381).

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No conflict of interest is declared.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical Research Center for Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea

    In-Ja Park, Woo Kyeom Yang, Sang-Hee Nam, Sung Soo Kim, Wonchae Choe, Insug Kang & Joohun Ha

  2. Department of Oral Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Joungmok Kim

  3. College of Pharmacy, Kyung Hee University, Seoul, 130-701, Republic of Korea

    Jongki Hong & Ki Ryeol Yang

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  1. In-Ja Park
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Correspondence to Joohun Ha.

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Park, IJ., Yang, W.K., Nam, SH. et al. Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma. Apoptosis 19, 615–628 (2014). https://doi.org/10.1007/s10495-013-0929-0

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