Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis
The nuclear receptors known as peroxisome proliferator activated receptor gamma (PPARG) are lipid-activated transcription factors that have emerged as key regulators of inflammation. PPARG ligands have been shown to have an anti-proliferative effect on a variety of cancers. These ligands can induce...
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2019.00554/full |
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| author | Simran Kaur Simran Kaur Alo Nag Gurudutta Gangenahalli Kulbhushan Sharma |
| author_facet | Simran Kaur Simran Kaur Alo Nag Gurudutta Gangenahalli Kulbhushan Sharma |
| author_sort | Simran Kaur |
| collection | DOAJ |
| description | The nuclear receptors known as peroxisome proliferator activated receptor gamma (PPARG) are lipid-activated transcription factors that have emerged as key regulators of inflammation. PPARG ligands have been shown to have an anti-proliferative effect on a variety of cancers. These ligands can induce apoptosis via TP53 (Tumor protein p53) or ERK1/2 (Extracellular signal-regulated kinases 1/2) (EPHB2) pathways. However, the exact mechanism is not known. PPAR, a type II nuclear hormone receptor deserves attention as a selective target for radiotherapy. Our study examines the potential of selective agonism of PPARG for radiation therapy in non-small cell lung carcinoma (NSCLC). We found that the overexpression of PPARG protein as well as its induction using the agonist, rosiglitazone was able to stimulate radiation-induced cell death in otherwise radio resistant NSCLC A549 cell line. This cell death was apoptotic and was found to be BAX (BCL2 associated X) mediated. The treatment also inhibited radiation-induced AKT (Protein Kinase B) phosphorylation. Interestingly, the ionising radiation (IR) induced apoptosis was found to be inversely related to TP53 levels. A relatively significant increase in the levels of radiation induced apoptosis was observed in H1299 cells (TP53 null) under PPARG overexpression condition further supporting the inverse relationship between apoptosis and TP53 levels. The combination of PPARG agonist and radiation was able to induce apoptosis at a radiation dose at which A549 and H1299 are radioresistant, thus confirming the potential of the combinatorial strategy. Taken together, PPARG agonism was found to invigorate the radiosensitising effect and hence its use in combination with radiotherapy is expected to enhance sensitivity in otherwise resistant cancer types. |
| first_indexed | 2024-12-23T02:59:49Z |
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| id | doaj.art-3cc6a423d32146dc96f6bbb8f83a40dd |
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| language | English |
| last_indexed | 2024-12-23T02:59:49Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-3cc6a423d32146dc96f6bbb8f83a40dd2022-12-21T18:02:27ZengFrontiers Media S.A.Frontiers in Genetics1664-80212019-06-011010.3389/fgene.2019.00554460211Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced ApoptosisSimran Kaur0Simran Kaur1Alo Nag2Gurudutta Gangenahalli3Kulbhushan Sharma4Division of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, New Delhi, IndiaDepartment of Biochemistry, University of Delhi, New Delhi, IndiaDepartment of Biochemistry, University of Delhi, New Delhi, IndiaDivision of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, New Delhi, IndiaDivision of Stem Cell and Gene Therapy Research, Institute of Nuclear Medicine and Allied Sciences, New Delhi, IndiaThe nuclear receptors known as peroxisome proliferator activated receptor gamma (PPARG) are lipid-activated transcription factors that have emerged as key regulators of inflammation. PPARG ligands have been shown to have an anti-proliferative effect on a variety of cancers. These ligands can induce apoptosis via TP53 (Tumor protein p53) or ERK1/2 (Extracellular signal-regulated kinases 1/2) (EPHB2) pathways. However, the exact mechanism is not known. PPAR, a type II nuclear hormone receptor deserves attention as a selective target for radiotherapy. Our study examines the potential of selective agonism of PPARG for radiation therapy in non-small cell lung carcinoma (NSCLC). We found that the overexpression of PPARG protein as well as its induction using the agonist, rosiglitazone was able to stimulate radiation-induced cell death in otherwise radio resistant NSCLC A549 cell line. This cell death was apoptotic and was found to be BAX (BCL2 associated X) mediated. The treatment also inhibited radiation-induced AKT (Protein Kinase B) phosphorylation. Interestingly, the ionising radiation (IR) induced apoptosis was found to be inversely related to TP53 levels. A relatively significant increase in the levels of radiation induced apoptosis was observed in H1299 cells (TP53 null) under PPARG overexpression condition further supporting the inverse relationship between apoptosis and TP53 levels. The combination of PPARG agonist and radiation was able to induce apoptosis at a radiation dose at which A549 and H1299 are radioresistant, thus confirming the potential of the combinatorial strategy. Taken together, PPARG agonism was found to invigorate the radiosensitising effect and hence its use in combination with radiotherapy is expected to enhance sensitivity in otherwise resistant cancer types.https://www.frontiersin.org/article/10.3389/fgene.2019.00554/fullPPARGradiosensitizationNSCLCBAXTP53Hedgehog signaling |
| spellingShingle | Simran Kaur Simran Kaur Alo Nag Gurudutta Gangenahalli Kulbhushan Sharma Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis Frontiers in Genetics PPARG radiosensitization NSCLC BAX TP53 Hedgehog signaling |
| title | Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis |
| title_full | Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis |
| title_fullStr | Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis |
| title_full_unstemmed | Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis |
| title_short | Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis |
| title_sort | peroxisome proliferator activated receptor gamma sensitizes non small cell lung carcinoma to gamma irradiation induced apoptosis |
| topic | PPARG radiosensitization NSCLC BAX TP53 Hedgehog signaling |
| url | https://www.frontiersin.org/article/10.3389/fgene.2019.00554/full |
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