Medizinische Universität Graz - Research portal
Selected Publication:
Jahn, N.
Prostaglandin 15d-PGJ2 induces downregulation of class III histone deacetylase SIRT1 in lung adenocarcinoma cells
[ Diplomarbeit/Master Thesis (UNI) ] Universität Graz; 2023.
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- Authors Med Uni Graz:
- Advisor:
- Hrzenjak Andelko
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- Abstract:
- Lung cancer has been the most prevalent cancer in the world and the main factor in mortality from cancer for a number of years. It is particularly critical that non-small cell lung cancers (NSCLCs) are frequently developing chemotherapy resistance. Therefore, there is a need for lung cancer treatment advancement and extension. In this study, we concentrate on the impact of 15-Deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2), a naturally occurring prostaglandin, on class III histone deacetylase SIRT1 as a potential therapeutic alternative for NSCLC patients. 15d- PGJ2 performs as a peroxisome proliferator-activated receptor gamma (PPARγ) endogenous ligand, which possesses anti-inflammatory and anticancer effects through PPARγ-dependent and/or PPARγ -independent mechanisms. The NAD+ -dependent deacetylase SIRT1 is a possible therapeutic target for activators and inhibitors as it modulates factors important in stress response and cell survival through deacetylation of important regulatory proteins. However, to be addressed in cancer therapy, it is crucial to understand the precise function and role of SIRT1 in tumor cells. Previous work from our group revealed that 15d-PGJ2 displayed significant anticancer action via decreasing cell motility and proliferation while inducing apoptosis in three NSCLC cell lines. The purpose of this project was to examine how 15d-PGJ2 affects SIRT1 protein expression in A549, H1299 and H23 lung cancer cells and whether inhibition of SIRT1 effects 15d-PGJ2 activity on apoptosis and cell viability. We also investigated the clonogenic ability of NSCLC cells with silenced SIRT1 compared to control NSCLC cells. Treatment with 15d-PGJ2 specifically reduced SIRT1 protein level expression in A549, H1299 and H23 cell lines in a time-dependent manner. Moreover, transient transfection of NSCLC cells with siRNA against SIRT1 significantly reduced SIRT1 expression at protein and mRNA levels representing the prerequisite for further experiments. We discovered that SIRT1 inhibition promoted 15d-PGJ2 induced apoptosis in A549 and minimally in H23, but not in H1299 lung cancer cells. Contrarily, 15d-PGJ2 treatment of H1299 cells stably transfected with SIRT1 shRNA led to improved cell viability, as compared to control cells, considering the use of possible SIRT1 activators in combination with 15d-PGJ2 treatment. Colony formation assay supported those findings. The inhibition of SIRT1 resulted in a higher clonogenic ability of A549, H1299 and H23 cells, meaning that SIRT1 suppresses cell proliferation in NSCLC cells. In summary, the use of SIRT1 activators and inhibitors in the 15d-PGJ2 treatment of NSCLC is justified in light of these findings, pointing out that additional research is required to gain a thorough understanding of the molecular SIRT1 pathways induced by 15d-PGJ2.