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Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells

Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells

Mitsunobu Takeda, Jun Koseki, Hidekazu Takahashi, Norikatsu Miyoshi, Naohiro Nishida, Junichi Nishimura, Taishi Hata, Chu Matsuda, Tsunekazu Mizushima, Hirofumi Yamamoto, Hideshi Ishii, Yuichiro Doki, Masaki Mori, etc.

Cancer Res. 2019 Apr 1;79(7):1426-1437.

PMID: 30765602

Abstract:

Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSCs remains promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSCs and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an antimalarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug. Endolysosomal RAB5/7 and LAMP1/2 mediated parkin-dependent mitochondrial clearance and modulated mitophagy through lysosomal dynamics. In a patient-derived xenograft (PDX) model of colon cancer, treatment with mefloquine resulted in suppression of mitophagic PINK1/PARKIN and increased mitochondrial disorder and mitochondria-induced apoptosis without apparent side effects. These results suggest that the combination of mefloquine with chemotherapeutic agents in the PDX model potentially disrupts the hierarchy of colorectal cancer cells and identify endolysosomal RAB5/7 and LAMP1/2 as promising therapeutic targets in CSCs. SIGNIFICANCE: These findings show that endosomal/lysosomal RAB5 and RAB7, which regulate mitophagy, are essential for the survival of colon cancer stem cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1426/F1.large.jpg.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP51773923-A	Mefloquine hydrochloride		51773-92-3	Price

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