Title:Autophagy Inhibition in Childhood Nephroblastoma and the Therapeutic Significance
Volume: 18
Issue: 3
Author(s): Lin-Jie Li , Yi-Long Wang, Lin-Qing Yuan, Wei-Zhong Gu, Kun Zhu, Min Yang, Duo Zhou, Yao Lv, Min-Ju Li, Zheng-Yan Zhao, Jin-Hu Wang*Xi Chen*
Affiliation:
- Oncology, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
- Key Laboratory of Diagnosis and Treatment of Neonatal Diseases of Zhejiang Province, Zhejiang,China
Keywords:
Nephroblastoma, Wilm's tumor, autophagy, Beclin 1, chemotherapy, combinational therapy.
Abstract: Background: Autophagy is a physiological pathway characterized by lysosomedependent
self-digestion to recycle damaged or superfluous cellular content. Deregulation of autophagy
hampers the maintenance of cellular homeostasis and contributes to tumorigenesis. However,
during anticancer therapy, autophagy activation contributes to development of resistance. Thus autophagy
has been recognized as an important pathway and a therapeutic target in cancer. Nephroblastoma
(Wilm's tumor) is a common childhood malignancy. The role of autophagy in nephroblastoma
is largely uninvestigated.
Objective: This study is to investigate the change of autophagy level in nephroblastoma, and whether
autophagy could be a therapeutic target in anaplastic nephroblastoma.
Method: In clinical samples of childhood nephroblastoma, autophagy activity was evaluated by the
expressions of selected autophagy markers as well as the presence of autophagosome ultrastructure.
Use of autophagy inhibitors alone and in combination with conventional chemotherapeutics, was
studied both in vivo and in vitro.
Results: In nephroblastoma, there was decrease in the Beclin 1 level and the number of autophagosomes,
suggesting autophagy inhibition. Furthermore, in two anaplastic nephroblastoma cell
lines, G401 and SK-NEP1, autophagy inhibitors further enhanced the efficacy of conventional chemotherapeutics
including vincristine and cisplatin. In G401 tumor model established in nude mice,
combinational use of chloroquine, an inhibitor of autophagy degradation, further decreased the tumor
mass compared with single use of the chemotherapeutics vindesine, although no statistical significance
was achieved.
Conclusion: Our results suggest that autophagy deregulation is involved in nephroblastoma, and
targeting autophagy can serve as a potential adjuvant strategy for the highly malignant cases.
