IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-44084-3.html
   My bibliography  Save this article

Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis

Author

Listed:
  • Nadege Gitego

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Bogos Agianian

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Oi Wei Mak

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Vasantha Kumar MV

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Emily H. Cheng

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • Evripidis Gavathiotis

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

Abstract

The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in apoptosis execution. Previous studies reported two inactive conformations of cytosolic BAX, a monomer and a dimer, however, it remains unclear how they regulate BAX. Here we show that, surprisingly, cancer cell lines express cytosolic inactive BAX dimers and/or monomers. Expression of inactive dimers, results in reduced BAX activation, translocation and apoptosis upon pro-apoptotic drug treatments. Using the inactive BAX dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic BAX dimers and prompts cells to apoptosis either alone or in combination with BCL-2/BCL-XL inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive BAX dimer in resistance to apoptosis and demonstrate a strategy to potentiate BAX-mediated apoptosis.

Suggested Citation

  • Nadege Gitego & Bogos Agianian & Oi Wei Mak & Vasantha Kumar MV & Emily H. Cheng & Evripidis Gavathiotis, 2023. "Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44084-3
    DOI: 10.1038/s41467-023-44084-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-44084-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-44084-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Andrea Lopez & Denis E. Reyna & Nadege Gitego & Felix Kopp & Hua Zhou & Miguel A. Miranda-Roman & Lars Ulrik Nordstrøm & Swathi-Rao Narayanagari & Ping Chi & Eduardo Vilar & Aristotelis Tsirigos & Evr, 2022. "Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Mahmoud Ghandi & Franklin W. Huang & Judit Jané-Valbuena & Gregory V. Kryukov & Christopher C. Lo & E. Robert McDonald & Jordi Barretina & Ellen T. Gelfand & Craig M. Bielski & Haoxin Li & Kevin Hu & , 2019. "Next-generation characterization of the Cancer Cell Line Encyclopedia," Nature, Nature, vol. 569(7757), pages 503-508, May.
    3. Evripidis Gavathiotis & Motoshi Suzuki & Marguerite L. Davis & Kenneth Pitter & Gregory H. Bird & Samuel G. Katz & Ho-Chou Tu & Hyungjin Kim & Emily H.-Y. Cheng & Nico Tjandra & Loren D. Walensky, 2008. "BAX activation is initiated at a novel interaction site," Nature, Nature, vol. 455(7216), pages 1076-1081, October.
    4. Adam Z. Spitz & Emmanouil Zacharioudakis & Denis E. Reyna & Thomas P. Garner & Evripidis Gavathiotis, 2021. "Eltrombopag directly inhibits BAX and prevents cell death," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Natalia Pardo-Lorente & Anestis Gkanogiannis & Luca Cozzuto & Antoni Gañez Zapater & Lorena Espinar & Ritobrata Ghose & Jacqueline Severino & Laura García-López & Rabia Gül Aydin & Laura Martin & Mari, 2024. "Nuclear localization of MTHFD2 is required for correct mitosis progression," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Manish Kumar & David Molkentine & Jessica Molkentine & Kathleen Bridges & Tongxin Xie & Liangpeng Yang & Andrew Hefner & Meng Gao & Reshub Bahri & Annika Dhawan & Mitchell J. Frederick & Sahil Seth & , 2021. "Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Feng Wang & Yang Xu & Robert Wang & Beatrice Zhang & Noah Smith & Amber Notaro & Samantha Gaerlan & Eric Kutschera & Kathryn E. Kadash-Edmondson & Yi Xing & Lan Lin, 2023. "TEQUILA-seq: a versatile and low-cost method for targeted long-read RNA sequencing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. C. Megan Young & Laurent Beziaud & Pierre Dessen & Angela Madurga Alonso & Albert Santamaria-Martínez & Joerg Huelsken, 2023. "Metabolic dependencies of metastasis-initiating cells in female breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Miquel Anglada-Girotto & Ludovica Ciampi & Sophie Bonnal & Sarah A. Head & Samuel Miravet-Verde & Luis Serrano, 2024. "In silico RNA isoform screening to identify potential cancer driver exons with therapeutic applications," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Andrea Lopez & Denis E. Reyna & Nadege Gitego & Felix Kopp & Hua Zhou & Miguel A. Miranda-Roman & Lars Ulrik Nordstrøm & Swathi-Rao Narayanagari & Ping Chi & Eduardo Vilar & Aristotelis Tsirigos & Evr, 2022. "Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Fei Li & Yizhe Wang & Inah Hwang & Ja-Young Jang & Libo Xu & Zhong Deng & Eun Young Yu & Yiming Cai & Caizhi Wu & Zhenbo Han & Yu-Han Huang & Xiangao Huang & Ling Zhang & Jun Yao & Neal F. Lue & Paul , 2023. "Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    9. Wei Hu & Yangjun Wu & Qili Shi & Jingni Wu & Deping Kong & Xiaohua Wu & Xianghuo He & Teng Liu & Shengli Li, 2022. "Systematic characterization of cancer transcriptome at transcript resolution," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Adrià Fernández-Torras & Miquel Duran-Frigola & Martino Bertoni & Martina Locatelli & Patrick Aloy, 2022. "Integrating and formatting biomedical data as pre-calculated knowledge graph embeddings in the Bioteque," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    11. Kazuya Tsujita & Reiko Satow & Shinobu Asada & Yoshikazu Nakamura & Luis Arnes & Keisuke Sako & Yasuyuki Fujita & Kiyoko Fukami & Toshiki Itoh, 2021. "Homeostatic membrane tension constrains cancer cell dissemination by counteracting BAR protein assembly," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    12. Nishanth Ulhas Nair & Patricia Greninger & Xiaohu Zhang & Adam A. Friedman & Arnaud Amzallag & Eliane Cortez & Avinash Das Sahu & Joo Sang Lee & Anahita Dastur & Regina K. Egan & Ellen Murchie & Miche, 2023. "A landscape of response to drug combinations in non-small cell lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    13. Yixiao Zhu & Chengmei Huang & Chao Zhang & Yi Zhou & Enen Zhao & Yaxin Zhang & Xingyan Pan & Huilin Huang & Wenting Liao & Xin Wang, 2023. "LncRNA MIR200CHG inhibits EMT in gastric cancer by stabilizing miR-200c from target-directed miRNA degradation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    14. Linhua Wang & Mirjana Maletic-Savatic & Zhandong Liu, 2022. "Region-specific denoising identifies spatial co-expression patterns and intra-tissue heterogeneity in spatially resolved transcriptomics data," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    15. Xiao Chen & Yinglu Li & Fang Zhu & Xinjing Xu & Brian Estrella & Manuel A. Pazos & John T. McGuire & Dimitris Karagiannis & Varun Sahu & Mustafo Mustafokulov & Claudio Scuoppo & Francisco J. Sánchez-R, 2023. "Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    16. Johanna Zerbib & Marica Rosaria Ippolito & Yonatan Eliezer & Giuseppina Feudis & Eli Reuveni & Anouk Savir Kadmon & Sara Martin & Sonia Viganò & Gil Leor & James Berstler & Julia Muenzner & Michael Mü, 2024. "Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    17. Claudia Capparelli & Timothy J. Purwin & McKenna Glasheen & Signe Caksa & Manoela Tiago & Nicole Wilski & Danielle Pomante & Sheera Rosenbaum & Mai Q. Nguyen & Weijia Cai & Janusz Franco-Barraza & Ric, 2022. "Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Ruitong Li & Olaf Klingbeil & Davide Monducci & Michael J. Young & Diego J. Rodriguez & Zaid Bayyat & Joshua M. Dempster & Devishi Kesar & Xiaoping Yang & Mahdi Zamanighomi & Christopher R. Vakoc & Ta, 2022. "Comparative optimization of combinatorial CRISPR screens," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    19. George Rosenberger & Wenxue Li & Mikko Turunen & Jing He & Prem S. Subramaniam & Sergey Pampou & Aaron T. Griffin & Charles Karan & Patrick Kerwin & Diana Murray & Barry Honig & Yansheng Liu & Andrea , 2024. "Network-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    20. Umberto Perron & Elena Grassi & Aikaterini Chatzipli & Marco Viviani & Emre Karakoc & Lucia Trastulla & Lorenzo M. Brochier & Claudio Isella & Eugenia R. Zanella & Hagen Klett & Ivan Molineris & Julia, 2024. "Integrative ensemble modelling of cetuximab sensitivity in colorectal cancer patient-derived xenografts," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44084-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.