The V-ATPase-inhibitor Archazolid abrogates tumor metastasis via inhibition of endocytic activation of the Rho-GTPase Rac1
Romina M. Wiedmann,Karin von Schwarzenberg,Andrea Palamidessi,Laura Schreiner,Rebekka Kubisch,Johanna Liebl,Christina Schempp,Dirk Trauner,György Vereb,Stefan Zahler,Ernst Wagner,Rolf Müller,Giorgio Scita,Angelika M. Vollmar +13 more
TLDR
The results indicate that archazolid effectively decreases metastatic dissemination of breast tumors by impairing the trafficking and spatially restricted activation of EGFR and Rho-GTPase Rac1, which are pivotal for directed movement of cells.Abstract:
The abundance of the multimeric vacuolar ATP-dependent proton pump, V-ATPase, on the plasma membrane of tumor cells correlates with the invasiveness of the tumor cell, suggesting the involvement of V-ATPase in tumor metastasis. V-ATPase is hypothesized to create a proton efflux leading to an acidic pericellular microenvironment that promotes the activity of proinvasive proteases. An alternative, not yet explored possibility is that V-ATPase regulates the signaling machinery responsible for tumor cell migration. Here, we show that pharmacologic or genetic reduction of V-ATPase activity significantly reduces migration of invasive tumor cells in vitro. Importantly, the V-ATPase inhibitor archazolid abrogates tumor dissemination in a syngeneic mouse 4T1 breast tumor metastasis model. Pretreatment of cancer cells with archazolid impairs directional motility by preventing spatially restricted, leading edge localization of epidermal growth factor receptor (EGFR) as well as of phosphorylated Akt. Archazolid treatment or silencing of V-ATPase inhibited Rac1 activation, as well as Rac1-dependent dorsal and peripheral ruffles by inhibiting Rab5-mediated endocytotic/exocytotic trafficking of Rac1. The results indicate that archazolid effectively decreases metastatic dissemination of breast tumors by impairing the trafficking and spatially restricted activation of EGFR and Rho-GTPase Rac1, which are pivotal for directed movement of cells. Thus, our data reveals a novel mechanism underlying the role of V-ATPase in tumor dissemination. Cancer Res; 72(22); 5976–87. ©2012 AACR.read more
Citations
More filters
Journal ArticleDOI
Acidic extracellular microenvironment and cancer
Yasumasa Kato,Shigeyuki Ozawa,Chihiro Miyamoto,Yojiro Maehata,Atsuko Suzuki,Toyonobu Maeda,Yuh Baba +6 more
TL;DR: CO2 from the pentose phosphate pathway is an alternative source of acidity, showing that hypoxia and extracellular acidity are, while being independent from each other, deeply associated with the cellular microenvironment.
Journal ArticleDOI
Recent Insights into the Structure, Regulation, and Function of the V-ATPases
TL;DR: Recent insights into their structure and mechanism, the mechanisms that regulate V-ATPase activity (particularly regulated assembly and trafficking), and the role of V- ATPases in processes such as cell signaling and cancer are highlighted.
Journal ArticleDOI
The Function of V-ATPases in Cancer
TL;DR: Of greatest excitement is evidence that at least some tumors express isoforms of V-ATPase subunits whose disruption is not lethal, leading to the possibility of developing anti-cancer therapeutics that selectively target V- ATPases that function in cancer cells.
Journal ArticleDOI
Regulation of Luminal Acidification by the V-ATPase
Sylvie Breton,Dennis Brown +1 more
TL;DR: This review focuses on the regulation of V-ATPase-dependent luminal acidification in renal intercalated cells and epididymal clear cells, which are key players in these physiological processes.
References
More filters
Journal ArticleDOI
A new mathematical model for relative quantification in real-time RT-PCR.
TL;DR: This study enters into the particular topics of the relative quantification in real-time RT-PCR of a target gene transcript in comparison to a reference gene transcript and presents a new mathematical model that needs no calibration curve.
Journal ArticleDOI
A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry
TL;DR: A flow cytometric method for measuring the percentage of apoptotic nuclei after propidium iodide staining in hypotonic buffer is developed and shown an excellent correlation with the results obtained with both electrophoretic and colorimetric methods.
Journal ArticleDOI
A Perspective on Cancer Cell Metastasis
TL;DR: It is suggested that metastasis can be portrayed as a two-phase process: the first phase involves the physical translocation of a cancer cell to a distant organ, whereas the second encompasses the ability of the cancer cellto develop into a metastatic lesion at that distant site.
Journal ArticleDOI
Twist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis
Jing Yang,Sendurai A. Mani,Joana Liu Donaher,Sridhar Ramaswamy,Sridhar Ramaswamy,Raphael Itzykson,Christophe Côme,Pierre Savagner,Inna Gitelman,Andrea L. Richardson,Robert A. Weinberg +10 more
TL;DR: A mechanistic link between Twist, EMT, and tumor metastasis is established, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT).
Journal ArticleDOI
Rab proteins as membrane organizers
Marino Zerial,Heidi M. McBride +1 more
TL;DR: Cellular organelles in the exocytic and endocytic pathways have a distinctive spatial distribution and communicate through an elaborate system of vesiculo-tubular transport.