Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment
| Autor: | Hong-Sheng Wang, Jun Du, Fang-Lan Liu, Hiroshi Kurihara, Huan Zhang, Liu Yang, Jun Xu, Enpan Mo, Shaohui Cai |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
autophagy Blotting Western ATG5 Apoptosis Breast Neoplasms SMAD Biology Protective Agents Real-Time Polymerase Chain Reaction Immunoenzyme Techniques Transforming Growth Factor beta1 Mice 03 medical and health sciences TGF-β1 Tumor Cells Cultured Tumor Microenvironment Animals Humans RNA Messenger Cell Proliferation Retrospective Studies Membrane Potential Mitochondrial Mice Inbred BALB C Tumor microenvironment Reverse Transcriptase Polymerase Chain Reaction Kinase Cell growth Autophagy Fibroblasts Xenograft Model Antitumor Assays Cell biology Gene Expression Regulation Neoplastic mitochondria Cell Transformation Neoplastic Phenotype 030104 developmental biology Oncology NIH 3T3 Cells Cancer-Associated Fibroblasts Female cancer-associated fibroblasts Signal Transduction Research Paper Transforming growth factor |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Fang-Lan Liu 1 , En-Pan Mo 1 , Liu Yang 1 , Jun Du 2 , Hong-Sheng Wang 2 , Huan Zhang 1 , Hiroshi Kurihara 1 , Jun Xu 1 , Shao-Hui Cai 1 1 Pharmacy College, Jinan University, Guangzhou 510632, China 2 Pharmacy College, Sun Yat-Sen University, Guangzhou 510405, China Correspondence to: Shao-Hui Cai, e-mail: csh5689@sina.com Jun Xu, e-mail: goldstar_8209@163.com Keywords: autophagy, TGF-β1, tumor microenvironment, mitochondria, cancer-associated fibroblasts Received: July 06, 2015 Accepted: December 02, 2015 Published: December 21, 2015 ABSTRACT Transforming growth factor-β1 (TGF-β1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-β1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-β1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-β1. We demonstrated that TGF-β1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-β1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-β1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-β type I receptor kinase inhibitor LY-2157299 blocked TGF-β1 induced these effects. Taken together, our results indicated that TGF-β/Smad autophagy was involved in TGF-β1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer. |
| Databáze: | OpenAIRE |
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