Ophiobolin A Covalently Targets Complex IV Leading to Mitochondrial Metabolic Collapse in Cancer Cells.

Autor:	Gowans FA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720 USA.; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA.; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Innovative Genomics Institute, Berkeley, CA 94704 USA.; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720 USA., Thach DQ; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA.; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA., Wang Y; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA.; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Innovative Genomics Institute, Berkeley, CA 94704 USA.; Novartis Institutes for BioMedical Research, Basel, Switzerland., Altamirano Poblano BE; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA.; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Innovative Genomics Institute, Berkeley, CA 94704 USA.; Novartis Institutes for BioMedical Research, Basel, Switzerland., Dovala D; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Novartis Institutes for BioMedical Research, Emeryville, CA 94608 USA., Tallarico JA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Novartis Institutes for BioMedical Research, Cambridge, MA 02139 USA., McKenna JM; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Novartis Institutes for BioMedical Research, Basel, Switzerland., Schirle M; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Novartis Institutes for BioMedical Research, Cambridge, MA 02139 USA., Maimone TJ; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA.; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA., Nomura DK; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720 USA.; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720 USA.; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720 USA.; Innovative Genomics Institute, Berkeley, CA 94704 USA.; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720 USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 09. Date of Electronic Publication: 2023 Mar 09.
DOI:	10.1101/2023.03.09.531918
Abstrakt:	Ophiobolin A (OPA) is a sesterterpenoid fungal natural product with broad anti-cancer activity. While OPA possesses multiple electrophilic moieties that can covalently react with nucleophilic amino acids on proteins, the proteome-wide targets and mechanism of OPA remain poorly understood in many contexts. In this study, we used covalent chemoproteomic platforms to map the proteome-wide reactivity of OPA in a highly sensitive lung cancer cell line. Among several proteins that OPA engaged, we focused on two targets-cysteine C53 of HIG2DA and lysine K72 of COX5A-that are part of complex IV of the electron transport chain and contributed significantly to the anti-proliferative activity. OPA activated mitochondrial respiration in a HIG2DA and COX5A-dependent manner, led to an initial spike in mitochondrial ATP, but then compromised mitochondrial membrane potential leading to ATP depletion. We have used chemoproteomic strategies to discover a unique anti-cancer mechanism of OPA through activation of complex IV leading to compromised mitochondrial energetics and rapid cell death. Competing Interests: Declaration of Interests JAT, JMK, MS, and DD are employees of Novartis Institutes for BioMedical Research. This study was funded by the Novartis Institutes for BioMedical Research and the Novartis-Berkeley Translational Chemical Biology Institute. DKN is a co-founder, shareholder, and on the scientific advisory boards for Frontier Medicines and Vicinitas Therapeutics. DKN is a member of the board of directors for Vicinitas Therapeutics. DKN is also on the scientific advisory boards of The Mark Foundation for Cancer Research, Photys Therapeutics, Apertor Pharmaceuticals, Ecto Therapeutics, Oerth Bio, and Chordia Therapeutics. DKN is also on the investment advisory board of Droia Ventures and a16z Bio. TJM is a scientific advisory board member of Vicinitas Therapeutics.
Databáze:	MEDLINE
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