Abstract
Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZβ to inhibit endosomal trafficking and metastasis.
Highlights
One of the most challenging questions in cancer treatment is tumor metastasis [1, 2]
Since impaired endosomal trafficking has been implicated in the carcinogenesis, e.g., metastasis, of malignant tumors [21, 22], we investigated the effect of V1, an inhibitor of endosomal trafficking [30, 31], on the viability, proliferation, and migration of several human or mouse cancer cell lines, e.g., 4T1, MDA-MB-231, 4T07, etc
V1 was identified by us as being autophagy and endosomal trafficking inhibitor, which is more potent than wellestablished autophagy/endosomal trafficking inhibitors such as chloroquine [31]
Summary
One of the most challenging questions in cancer treatment is tumor metastasis [1, 2]. The maturation, sorting, and trafficking events of these vesicles are all tightly controlled by RAB small GTPases (RABs), membrane tethering complexes, SNAREs, and sorting nexin family proteins, as well as phosphatidylinositol phospholipids (PIPs) and their catalyzing enzymes [12,13,14,15]. The interplay among these complexes in regulating endosomal trafficking remains to be elucidated [14, 16]. We showed that V1 is a potent antimetastatic drug, but more importantly, we demonstrated that this drug inhibits metastasis by inhibiting endocytosis as it over-activates RAB5 by targeting CapZβ
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