Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting

Beatrice Parma, Vignesh Ramesh, Paradesi Naidu Gollavilli, Aarif Siddiqui, Luisa Pinna, Annemarie Schwab, Sabine Marschall, Shuman Zhang, Christian Pilarsky, Francesca Napoli, Marco Volante, Sophia Urbanczyk, Dirk Mielenz, Henrik Daa Schrøder, Marc Stemmler, Heiko Wurdak, Paolo Ceppi*

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Abstrakt

Background: The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures. Methods: Gene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9. Results: We show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients’ prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B. Conclusions: These results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.

OriginalsprogEngelsk
Artikelnummer248
TidsskriftJournal of Experimental and Clinical Cancer Research
Vol/bind40
Udgave nummer1
Antal sider20
ISSN1756-9966
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
This work was supported by the Interdisciplinary Center for Clinical Research of the University of Erlangen-Nuremberg (PC) and the German Research Foundation grant DFG-CE-281/5–1 (PC; BP). A. Siddiqui is supported by the Independent Research Fund Denmark grant number 0134-00012B to PC. CP is supported by the European Research Council (MSCA-ITN-ETN PRECODE 861196).

Publisher Copyright:
© 2021, The Author(s).

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