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Inhibition of JNJ-26481585-mediated autophagy induces apoptosis via ROS activation and mitochondrial membrane potential disruption in neuroblastoma cells

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Abstract

Neuroblastoma (NB) is the common pediatric tumor of the sympathetic nervous system characterized by poor prognosis. Owing to the challenges such as high tumor heterogeneity, multidrug resistance, minimal residual disease, etc., there is an immediate need for exploring new therapeutic strategies and effective treatments for NB. Herein, in the current study, we explored the unexplored response of NB cells to the second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585(JNJ) and the lysosomotropic agent, Chloroquine (CQ) alone and upon JNJ/CQ treatment as a plausible therapeutic. We identify that while JNJ alone induced autophagy in NB cells, JNJ/CQ treatment decreased the viability and proliferation of NB cells in vitro by switching from autophagy to apoptosis. Further we found that autophagy inhibition by CQ pre-treatment led to the generation of ROS and a decrease in the mitochondrial membrane potential (MMP) that subsequently caused caspase-3-mediated apoptotic cell death in NB cells. Corroborating the above observations, we found that the ROS scavenger N-acetylcysteine (NAC) countered caspase-3 activity and the cells were rescued from apoptosis. Finally, these observations establish that JNJ/CQ treatment resulted in cell death in NB cells by triggering the formation of ROS and disruption of MMP, suggesting that modulation of JNJ-induced autophagy by CQ represents a promising new therapeutic approach in NB.

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Acknowledgements

VKK thanks University Grants Commission (UGC) (Award No.22/06/2014 (i) EU-r) & DK thanks Council of Scientific & Industrial Research (CSIR) for SRF (Award No. 31/14(2691/2017-EMR-I). CSIR- IICT Manuscript communication No. is IICT/Pubs./2019/072.

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Authors and Affiliations

  1. Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana, 500007, India

    Vamsi Krishna Kommalapati, Dinesh Kumar & Anjana Devi Tangutur

  2. Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India

    Vamsi Krishna Kommalapati, Dinesh Kumar & Anjana Devi Tangutur

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  1. Vamsi Krishna Kommalapati
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VKK planned, designed the experiments, collected, and analyzed the data. DK validated the results and repeated the experiments. ADT conceived and supervised the research work, interpreted the data, and drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Anjana Devi Tangutur.

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Kommalapati, V.K., Kumar, D. & Tangutur, A.D. Inhibition of JNJ-26481585-mediated autophagy induces apoptosis via ROS activation and mitochondrial membrane potential disruption in neuroblastoma cells. Mol Cell Biochem 468, 21–34 (2020). https://doi.org/10.1007/s11010-020-03708-8

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