Autophagy is associated with chemoresistance in neuroblastoma
| Autor: | Pierre Teira, Roxane Le Gall, Assila Belounis, Gilles Vassal, Sonia Cournoyer, Hervé Sartelet, Carine Nyalendo, Tina V. Imbriglio, Mohamed Mahma, Elie Haddad, Mona Beaunoyer |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Oncology Cancer Research Autophagy-Related Protein 5 Neuroblastoma Gene Knockout Techniques Mice 0302 clinical medicine RNA Small Interfering Child Mice Knockout Immunohistochemistry Child Preschool 030220 oncology & carcinogenesis Disease Progression Chemoresistance Research Article Hydroxychloroquine medicine.drug medicine.medical_specialty Vincristine ATG5 Antineoplastic Agents 03 medical and health sciences Cell Line Tumor Internal medicine Autophagy medicine Genetics Animals Humans Doxorubicin Cell Proliferation Neoplasm Staging Cisplatin Cell growth business.industry Infant Newborn Infant medicine.disease Disease Models Animal 030104 developmental biology Drug Resistance Neoplasm Tumor progression Cancer research business Biomarkers Follow-Up Studies |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/s12885-016-2906-9 |
| Popis: | Background Neuroblastoma (NB) is a frequent pediatric tumor characterized by a poor prognosis where a majority of tumors progress despite intensive multimodality treatments. Autophagy, a self-degradative process in cells, could be induced by chemotherapy and be associated with chemoresistance. The aim of this study was to determine whether: 1) autophagy is present in NB, 2) chemotherapy modified its levels, and 3) its inhibition decreased chemoresistance. Methods Immunohistochemical stainings were performed on samples from 184 NB patients in order to verify the expression of LC3B, a specific marker for autophagy, and Beclin 1, a positive regulator of autophagy. In addition, we performed an in vitro study with six NB cell lines and six drugs (vincristine, doxorubicin, cisplatin temozolomide, LY294002 and syrolimus). Inhibition of autophagy was performed using ATG5 knockdown cells or hydroxychloroquine (HCQ). Cell survival was measured using the MTT cell proliferation assay. Autophagy was detected by monodansylcadaverine, confocal microscopy and Western blot. In vivo study with tumor xenografts in NSG mice was performed. Results Our results have indicated that autophagy was present at low levels in NB and was not a prognostic factor, while Beclin 1 was highly expressed in children with poor NB prognosis. However, autophagy levels increased after chemotherapy in vitro and in vivo. Tumor progression was significantly decreased in mice treated with a combination of HCQ and vincristine. Conclusions Taken together, autophagy is present in NB, induced by chemotherapy and associated with chemoresistance, which is significantly reduced by its inhibition. Therefore, targeting autophagy represents a very attractive approach to develop new therapeutic strategies in NB. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2906-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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