Disruption of lysosome function promotes tumor growth and metastasis in Drosophila.
Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras(V12) cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras(V12) cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras(V12) cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.
Chi
Congwu
C
Institute of Developmental Biology and Molecular Medicine, Fudan-Yale Center for Biomedical Research, School of Life Science, Fudan University, Shanghai 200433, China.
Zhu
Huanhu
H
Han
Min
M
Zhuang
Yuan
Y
Wu
Xiaohui
X
Xu
Tian
T
D000818:Animals; D002738:Chloroquine / Q000737:chemistry; D003433:Crosses, Genetic; D004330:Drosophila / Q000235:genetics*; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008957:Models, Genetic; D008985:Monensin / Q000737:chemistry; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D034622:RNA Interference; D033921:Vesicular Transport Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C424437:VPS18 protein, human; D033921:Vesicular Transport Proteins; D049452:Green Fluorescent Proteins; D002738:Chloroquine; D008985:Monensin; D018631:ras Proteins