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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

01-12-2021 | NSCLC | Research

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

Authors: 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

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

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.
Appendix
Available only for authorised users
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Metadata
Title
Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting
Authors
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
Publication date
01-12-2021
Publisher
BioMed Central
Keywords
NSCLC
NSCLC
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02049-8

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