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Autophagy Inhibition in Childhood Nephroblastoma and the Therapeutic Significance
Lin-Jie Li1, Yi-Long Wang1, Lin-Qing Yuan1
1Departments of Central Laboratory, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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.
Insights
Autophagy, a cellular recycling process, is altered in nephroblastoma, a childhood cancer. Inhibiting autophagy enhances chemotherapy effectiveness, suggesting it as a potential therapeutic target for aggressive cases.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Autophagy is a cellular degradation process crucial for homeostasis.
- Dysregulated autophagy is implicated in cancer development and therapy resistance.
- The role of autophagy in nephroblastoma (Wilm's tumor) remains largely unexplored.
Purpose of the Study:
- To investigate autophagy levels in nephroblastoma.
- To determine if autophagy can be a therapeutic target in anaplastic nephroblastoma.
Main Methods:
- Assessed autophagy markers and autophagosome ultrastructure in clinical nephroblastoma samples.
- Evaluated autophagy inhibitors alone and with chemotherapy in vitro and in vivo.
- Utilized anaplastic nephroblastoma cell lines (G401, SK-NEP1) and a G401 mouse model.
Main Results:
- Nephroblastoma showed reduced Beclin 1 levels and autophagosomes, indicating autophagy inhibition.
- Autophagy inhibitors potentiated chemotherapy (vincristine, cisplatin) in G401 and SK-NEP1 cells.
- Chloroquine combined with chemotherapy reduced tumor mass in a mouse model, though not statistically significant.
Conclusions:
- Autophagy deregulation is involved in nephroblastoma.
- Targeting autophagy presents a potential adjuvant strategy for aggressive nephroblastoma cases.