PPARγ activation induces autophagy in breast cancer cells |
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| Authors: | Jie Zhou Wei Zhang Bing Liang Mathew C. Casimiro Diana Whitaker-Menezes Min Wang Michael P. Lisanti Susan Lanza-Jacoby Richard G. Pestell Chenguang Wang |
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| Affiliation: | 1. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA;2. Center for Stem Cell Biology and Regenerative Medicine Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA;3. Department of Surgery, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA;4. Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China;5. Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China;1. Department of Oncology, People''s Hospital of Banan District, Chongqing, China;2. Department of Oncology, Traditional Chinese Medicine Integrated Western Medicine Hospital, Dazhou, Sichuan Province, China;3. Department of Thoracic Surgery, Tongchuan District, Dazhou, Sichuan Province, China;1. Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;2. Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;3. Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;4. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;5. Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;6. Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA |
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| Abstract: | It has been previously shown that PPARγ ligands induce apoptotic cell death in a variety of cancer cells. Given the evidence that these ligands have a receptor-independent function, we further examined the specific role of PPARγ activation in this biological process. Surprisingly, we failed to demonstrate that MDA-MB-231 breast cancer cells undergo apoptosis when treated with sub-saturation doses of troglitazone and rosiglitazone, which are synthetic PPARγ ligands. Acridine orange (AO) staining showed acidic vesicular formation within ligand-treated cells, indicative of autophagic activity. This was confirmed by autophagosome formation as indicated by redistribution of LC3, an autophagy-specific protein, and the appearance of double-membrane autophagic vacuoles by electron microscopy following exposure to ligand. To determine the mechanism by which PPARγ induces autophagy, we transduced primary mammary epithelial cells with a constitutively active mutant of PPARγ and screened gene expression associated with PPARγ activation by genome-wide array analysis. HIF1α and BNIP3 were among 42 genes up-regulated by active PPARγ. Activation of PPARγ induced HIF1α and BNIP3 protein and mRNA abundance. HIF1α knockdown by shRNA abolished the autophagosome formation induced by PPARγ activation. In summary, our data shows a specific induction of autophagy by PPARγ activation in breast cancer cells providing an understanding of distinct roles of PPARγ in tumorigenesis. |
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| Keywords: | PPARγ Autophagy Breast cancer HIF1α BNIP3 |
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