Autophagy is associated with chemoresistance in neuroblastoma

BMC Cancer

Research Article

Carine Nyalendo¹  Gilles Vassal²  Mona Beaunoyer³  Pierre Teira⁴  Roxane Le Gall⁵  Tina V. Imbriglio⁵  Mohamed Mahma⁵  Sonia Cournoyer⁵  Elie Haddad⁵  Assila Belounis⁶  Hervé Sartelet⁷ 

[1] Department of biochemistry, CHU Sainte Justine, Montreal, QC, Canada;Department of paediatric oncology, Institut Gustave Roussy, Villejuif, France;Department of surgery, CHU Sainte Justine, 3175, Montreal, QC, Canada;Division of paediatric oncology, CHU Sainte Justine, Montreal, QC, Canada;Research centre of the Sainte Justine university hospital, Montreal, QC, Canada;Research centre of the Sainte Justine university hospital, Montreal, QC, Canada;Department of pathology and cellular biology, Université de Montréal, Montreal, QC, Canada;Research centre of the Sainte Justine university hospital, Montreal, QC, Canada;Department of pathology and cellular biology, Université de Montréal, Montreal, QC, Canada;Department of pathology and cytogenetic, CHU Sainte Justine, Montreal, QC, Canada;

关键词: Neuroblastoma;    Autophagy;    Chemoresistance;    Hydroxychloroquine;   

DOI  :  10.1186/s12885-016-2906-9

 received in 2016-04-04, accepted in 2016-10-27,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundNeuroblastoma (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.MethodsImmunohistochemical 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.ResultsOur 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.ConclusionsTaken 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.

【 授权许可】

CC BY   
© The Author(s). 2016