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NVP-BEZ235, a dual PI3K/mTOR inhibitor, induces cell death through alternate routes in prostate cancer cells depending on the PTEN genotype

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Abstract

Deregulation of the PI3K-AKT/mTOR pathway due to mutation of the tumor suppressor gene PTEN frequently occurs in human prostate cancer and is therefore considered to be an attractive therapeutic target. Here, we investigated how the PTEN genotype affected the antitumor effect of NVP-BEZ235 in human prostate cancer cells. In this setting, NVP-BEZ235 induced cell death in a PTEN-independent manner. NVP-BEZ235 selectively induced apoptotic cell death in the prostate cancer cell line DU145, which harbors wild-type PTEN; however, in the PC3 cell line, which is PTEN-null, treatment with NVP-BEZ235 resulted in autophagic cell death. Consistently, NVP-BEZ235 treatment did not result in the cleavage of caspase-3; instead, it resulted in the conversion of LC3-I to LC3-II, indicating autophagic cell death; these results suggest that an alternate mechanism of cell death is induced by NVP-BEZ235 in PTEN-null prostate cancer cells. Based on our findings, we conclude that the PTEN/PI3K/Akt pathway is critical for prostate cancer survival, and targeting PI3K signaling by NVP-BEZ235 may be beneficial in the treatment of prostate cancer, independent of the PTEN genotype.

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Acknowledgments

This study was supported by grants from the Korea Health 21 R&D Project, Ministry of Health and Welfare and Family Affairs (HI10C2014), the Converging Research Center Program of the Ministry of Education, Science and Technology (2011K000871), and the Basic Science Research program through the National Research Foundation of Korea (NRF), which was funded by the Ministry of Education, Science and Technology (2012R1A1A2009160), Republic of Korea. This study was supported by a grant (2011-506) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea. We would like to thank Dr. Jaeyoung Koh, Department of Neurology, Asan Medical Center, for providing the GFP-LC3 cDNA.

Conflict of interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Republic of Korea

    Seung-Woo Hong, Jae-Sik Shin, Jai-Hee Moon, Ye-Seul Kim, Jooyoung Lee, Eun Kyoung Choi, Seung-Hee Ha, Dae Hee Lee, Ha Na Chung, Jeong Eun Kim, Kyu-pyo Kim, Yong Sang Hong, Jae-Lyun Lee, Eun Kyung Choi, Jung Shin Lee, Dong-Hoon Jin & Tae Won Kim

  2. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Republic of Korea

    Seung-Woo Hong, Jae-Sik Shin, Jai-Hee Moon, Ye-Seul Kim, Jooyoung Lee, Eun Kyoung Choi, Seung-Hee Ha, Dae Hee Lee, Ha Na Chung, Jeong Eun Kim, Kyu-pyo Kim, Yong Sang Hong, Jae-Lyun Lee, Jung Shin Lee, Dong-Hoon Jin & Tae Won Kim

  3. Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Republic of Korea

    Eun Kyung Choi

  4. Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, 110-744, Republic of Korea

    Wang-Jae Lee

  5. Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea

    Dae Hee Lee

  6. Department of Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Republic of Korea

    Dong-Hoon Jin

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  1. Seung-Woo Hong
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  16. Jung Shin Lee
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  17. Dong-Hoon Jin
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  18. Tae Won Kim
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Corresponding authors

Correspondence to Dong-Hoon Jin or Tae Won Kim.

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Seung-Woo Hong, Jae-Sik Shin, Jai-Hee Moon have contributed equally to this work.

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Hong, SW., Shin, JS., Moon, JH. et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, induces cell death through alternate routes in prostate cancer cells depending on the PTEN genotype. Apoptosis 19, 895–904 (2014). https://doi.org/10.1007/s10495-014-0973-4

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