التفاصيل البيبلوغرافية
| العنوان: |
Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting. |
| المؤلفون: |
Parma, Beatrice, Ramesh, Vignesh, Gollavilli, Paradesi Naidu, Siddiqui, Aarif, Pinna, Luisa, Schwab, Annemarie, Marschall, Sabine, Zhang, Shuman, Pilarsky, Christian, Napoli, Francesca, Volante, Marco, Urbanczyk, Sophia, Mielenz, Dirk, Schrøder, Henrik Daa, Stemmler, Marc, Wurdak, Heiko, Ceppi, Paolo |
| المصدر: |
Journal of Experimental & Clinical Cancer Research (17569966); 11/6/2021, Vol. 40 Issue 1, p1-20, 20p |
| مصطلحات موضوعية: |
CYTOCHROME oxidase, NON-small-cell lung carcinoma, METABOLIC flux analysis, HEAT shock proteins, SUBCUTANEOUS injections, THERAPEUTICS |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
|
Copyright of Journal of Experimental & Clinical Cancer Research (17569966) is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
Full Text Finder