Abstract
Simple SummaryNumerous studies targeting Rab GTPases and its multiple effectors have been attempted since exocytosis has been shown to alter tumor malignancy by modulating cancer cell behavior and tumor microenvironment. Here, we demonstrated that BHMPS inhibits migration and invasion of breast cancer cells by blocking the interaction between Rab27a and Slp4. BHMPS interfered with vesicle trafficking and secretion by decreasing FAK and JNK activation. In addition, BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. This study highlighted the importance of understanding the mechanisms of Rab27a-mediated metastasis in improving the therapeutic options for metastatic cancers.Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis.
Highlights
Metastasis is a crucial process in cancer development and is considered a leading cause of cancer therapy failure; its control remains a challenge
Intrinsic expression of Rab27a protein was higher in MDA-MB-231 and BT549 cells than in BT474 and MCF7 cells (Figure 1A)
MCF7 cells showed the lowest 50% growth inhibition (GI50) value of 18.62 μM, whereas BHMPS below 10 μM did not inhibit the growth of other breast cancer cells
Summary
Metastasis is a crucial process in cancer development and is considered a leading cause of cancer therapy failure; its control remains a challenge. EMT is a biological process by which epithelial cells are transformed into a mesenchymal state and is strongly associated with the development toward an advanced cancer phenotype During this process, cancer cells release several factors, including growth factors, chemokines, cytokines, and exosomes, to create a tumor microenvironment (TME) favorable for their survival [1,2]. Rab GTPases constitute a large family of small GTPases that regulate membrane identity and vesicle budding, uncoating, motility, and fusion, through complexing with effector proteins such as sorting adaptors, tethering factors, kinases, and phosphatases These Rab proteins primarily mediate the trafficking of proteins and organelles involved in cell growth, survival, and motility [3,4]. Many researchers have focused on targeting vesicle trafficking and exocytosis pathways because blocking exocytosis may provide novel therapeutic interventions, as it inhibits metastatic cancer and improves cancer therapeutic efficacy [12]
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