TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion
Abstract Background Glioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence...
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| Format: | Article |
| Language: | English |
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BMC
2017-11-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-017-0628-8 |
| _version_ | 1828392102548996096 |
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| author | Chao Zhang Xin Zhang Ran Xu Bin Huang An-Jing Chen Chao Li Jian Wang Xin-Gang Li |
| author_facet | Chao Zhang Xin Zhang Ran Xu Bin Huang An-Jing Chen Chao Li Jian Wang Xin-Gang Li |
| author_sort | Chao Zhang |
| collection | DOAJ |
| description | Abstract Background Glioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood. Methods U251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. Results Here we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better “turn off” tumor growth. Conclusion Our findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion. |
| first_indexed | 2024-12-10T07:15:37Z |
| format | Article |
| id | doaj.art-5a76c273bcbf48aba9bc15082fe5002b |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T07:15:37Z |
| publishDate | 2017-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-5a76c273bcbf48aba9bc15082fe5002b2022-12-22T01:57:57ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-11-0136111510.1186/s13046-017-0628-8TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasionChao Zhang0Xin Zhang1Ran Xu2Bin Huang3An-Jing Chen4Chao Li5Jian Wang6Xin-Gang Li7Department of Neurosurgery, Qilu Hospital of Shandong UniversityDepartment of Neurosurgery, Qilu Hospital of Shandong UniversityDepartment of Neurosurgery, Qilu Hospital of Shandong UniversityBrain Science Research Institute, Shandong UniversityBrain Science Research Institute, Shandong UniversityDepartment of Neurosurgery, Qilu Hospital of Shandong UniversityDepartment of Neurosurgery, Qilu Hospital of Shandong UniversityDepartment of Neurosurgery, Qilu Hospital of Shandong UniversityAbstract Background Glioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood. Methods U251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models. Results Here we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better “turn off” tumor growth. Conclusion Our findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion.http://link.springer.com/article/10.1186/s13046-017-0628-8Malignant brain tumorAutophagyTGF-βTumor invasionGalunisertib |
| spellingShingle | Chao Zhang Xin Zhang Ran Xu Bin Huang An-Jing Chen Chao Li Jian Wang Xin-Gang Li TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion Journal of Experimental & Clinical Cancer Research Malignant brain tumor Autophagy TGF-β Tumor invasion Galunisertib |
| title | TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion |
| title_full | TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion |
| title_fullStr | TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion |
| title_full_unstemmed | TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion |
| title_short | TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion |
| title_sort | tgf β2 initiates autophagy via smad and non smad pathway to promote glioma cells invasion |
| topic | Malignant brain tumor Autophagy TGF-β Tumor invasion Galunisertib |
| url | http://link.springer.com/article/10.1186/s13046-017-0628-8 |
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