Therapeutic advantage of targeting lysosomal membrane integrity supported by lysophagy in malignant glioma

• Published in: Cancer science Vol. 113; no. 8; pp. 2716 - 2726
• Main Authors: Jing, Yongwei, Kobayashi, Masahiko, Vu, Ha Thi, Kasahara, Atsuko, Chen, Xi, Pham, Loc Thi, Kurayoshi, Kenta, Tadokoro, Yuko, Ueno, Masaya, Todo, Tomoki, Nakada, Mitsutoshi, Hirao, Atsushi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-08-2022; John Wiley and Sons Inc
• Subjects: Autophagy; Blood-brain barrier; Brain cancer; calcium; Calcium (intracellular); Calcium (mitochondrial); Central nervous system; Chemical compounds; Chloroquine; Comparative analysis; Cytotoxicity; Endoplasmic reticulum; Enzymes; FDA approval; Flow cytometry; Glioblastoma; Glioma; Infections; lysosomal membrane integrity; lysosomal membrane turnover; Lysosomes; Macromolecules; Membrane proteins; Mitochondria; Nervous system; Neural stem cells; Original; ORIGINAL ARTICLES; Progenitor cells; Proteins; Quality control; Reactive oxygen species; Therapeutic targets; Tumors; Xenografts; Lysosomal membrane turnover; autophagy; calcium; glioblastoma; lysosomal membrane integrity
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15451

Lysosomes function as the digestive system of a cell and are involved in macromolecular recycling, vesicle trafficking, metabolic reprogramming, and progrowth signaling. Although quality control of lysosome biogenesis is thought to be a potential target for cancer therapy, practical strategies have not been established. Here, we show that lysosomal membrane integrity supported by lysophagy, a selective autophagy for damaged lysosomes, is a promising therapeutic target for glioblastoma (GBM). In this study, we found that ifenprodil, an FDA‐approved drug with neuromodulatory activities, efficiently inhibited spheroid formation of patient‐derived GBM cells in a combination with autophagy inhibition. Ifenprodil increased intracellular Ca2+ level, resulting in mitochondrial reactive oxygen species–mediated cytotoxicity. The ifenprodil‐induced Ca2+ elevation was due to Ca2+ release from lysosomes, but not endoplasmic reticulum, associated with galectin‐3 punctation as an indicator of lysosomal membrane damage. As the Ca2+ release was enhanced by ATG5 deficiency, autophagy protected against lysosomal membrane damage. By comparative analysis of 765 FDA‐approved compounds, we identified another clinically available drug for central nervous system (CNS) diseases, amoxapine, in addition to ifenprodil. Both compounds promoted degradation of lysosomal membrane proteins, indicating a critical role of lysophagy in quality control of lysosomal membrane integrity. Importantly, a synergistic inhibitory effect of ifenprodil and chloroquine, a clinically available autophagy inhibitor, on spheroid formation was remarkable in GBM cells, but not in nontransformed neural progenitor cells. Finally, chloroquine dramatically enhanced effects of the compounds inducing lysosomal membrane damage in a patient‐derived xenograft model. These data demonstrate a therapeutic advantage of targeting lysosomal membrane integrity in GBM.
Quality control of lysosome biogenesis is thought to be a potential target for cancer therapy, however, practical strategies have not been established. Here, we show that lysosomal membrane integrity supported by lysophagy, a selective autophagy for damaged lysosomes, is a promising therapeutic target for malignant brain tumor.