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Published on: July 21, 2018
Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting
Beatrice Parma1, Vignesh Ramesh1, Paradesi Naidu Gollavilli1
1Interdisciplinary Center for Clinical Research (IZKF), Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
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.
Insights
Heat shock protein D1 (HSPD1) is a survival gene in non-small cell lung cancer (NSCLC). Targeting HSPD1 disrupts cell metabolism and proliferation, offering a new therapeutic strategy for NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide.
- Targeting metabolic alterations in cancer cells offers therapeutic potential.
- Heat shock proteins (HSPs) are crucial for metabolic enzyme function and cellular fitness.
Purpose of the Study:
- To identify novel therapeutic targets for NSCLC.
- To investigate the role of heat shock proteins in NSCLC metabolism and progression.
- To evaluate HSPD1 as a potential therapeutic target and theranostic marker.
Main Methods:
- Bioinformatic analysis of gene fitness from genetic screening datasets.
- Immunohistochemistry to assess HSPD1 expression in NSCLC patient tissues.
- In vitro and in vivo assays to monitor cell proliferation and drug sensitivity.
- Extracellular metabolic flux analysis and CRISPR/Cas9 gene editing.
Main Results:
- HSPD1 (HSP60) is identified as a survival gene in NSCLC, associated with poor patient prognosis.
- HSPD1 knockdown or inhibition with KHS101 disrupts oxidative phosphorylation and suppresses tumor growth.
- HSPD1-targeted effects depend on oxidative phosphorylation and are influenced by SLC6A8 and COX5B expression.
Conclusions:
- Mitochondrial metabolism is a promising target for NSCLC therapy.
- HSPD1 serves as a potential theranostic marker for NSCLC treatment development.
