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Translational Therapeutics

Bcl-2-dependent synthetic lethal interaction of the IDF-11774 with the V0 subunit C of vacuolar ATPase (ATP6V0C) in colorectal cancer

British Journal of Cancervolume 119pages13471357 (2018) | Download Citation


The IDF-11774, a novel clinical candidate for cancer therapy, targets HSP70 and inhibits mitochondrial respiration, resulting in the activation of AMPK and reduction in HIF-1α accumulation.


To identify genes that have synthetic lethality to IDF-11774, RNA interference screening was conducted, using pooled lentiviruses expressing a short hairpin RNA library.


We identified ATP6V0C, encoding the V0 subunit C of lysosomal V-ATPase, knockdown of which induced a synergistic growth-inhibitory effect in HCT116 cells in the presence of IDF-11774. The synthetic lethality of IDF-11774 with ATP6V0C possibly correlates with IDF-11774-mediated autolysosome formation. Notably, the synergistic effect of IDF-11774 and the ATP6V0C inhibitor, bafilomycin A1, depended on the PIK3CA genetic status and Bcl-2 expression, which regulates autolysosome formation and apoptosis. Similarly, in an experiment using conditionally reprogramed cells derived from colorectal cancer patients, synergistic growth inhibition was observed in cells with low Bcl-2 expression.


Bcl-2 is a biomarker for the synthetic lethal interaction of IDF-11774 with ATP6V0C, which is clinically applicable for the treatment of cancer patients with IDF-11774 or autophagy-inducing anti-cancer drugs.

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This work was supported by the KRIBB Initiative program (KGM4751713), National Research Foundation (NRF) (NRF-2017R1A2B2011936 and NRF-2018R1A5A2023127) and Health Technology R&D (HI13C2162).

Authors contributions

B-K.K. designed and performed experiments and wrote part of manuscript. S.W.N. provided an initial idea and designed experiments. B.S.M. provided cancer patient-derived cell lines. HSB, J-Y.I. and J.P. performed experiment. K.L. synthesized IDF-11774. JL helped shRNA screening experiment. S-Y.K. and MK analyzed the hi-seq data of shRNA screening. H.L. and S.P. reviewed manuscript. M.W. advised all experiment and wrote a manuscript.

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Author notes

  1. These authors contributed equally: Bo-Kyung Kim, Soon Woo Nam, Byung Soh Min


  1. Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea

    • Bo-Kyung Kim
    • , Joo-Young Im
    • , Youngjoo Lee
    • , Seon-Young Kim
    • , Mirang Kim
    •  & Misun Won
  2. The Catholic University of Korea, Incheon St Mary’s Hospital, 56 Dongsuro Bupyunggu, Incheon, 06591, Korea

    • Soon Woo Nam
  3. Serverance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Korea

    • Byung Soh Min
    •  & Soonmyung Paik
  4. Metabolic Regulation Research Center, KRIBB, Daejeon, 34141, Korea

    • Hyun Seung Ban
  5. College of Pharmacy, Dongguk University-Seoul, Goyang, 410-820, Korea

    • Kyeong Lee
  6. Drug Discovery Team, ILDONG Pharmaceutical Co. Ltd., Hwaseong, Hwaseong, 445-811, Korea

    • Joon-Tae Park
    •  & Hongsub Lee
  7. Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Korea, Daejeon, 34113, Korea

    • Misun Won


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Ethics approval

All animal experimental protocols were approved by the Bioethics Committee of the Korea Research Institute of Bioscience and Biotechnology.

Competing interests

The authors declare no competing interests.


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

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Correspondence to Misun Won.

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