V-ATPase Inhibition Regulates Anoikis Resistance and Metastasis of Cancer Cells

Abstract

Fighting metastasis is a major challenge in cancer therapy and novel therapeutic targets and drugs are highly appreciated. Resistance of invasive cells to anoikis, a particular type of apoptosis induced by loss of cell-matrix contact, is a major prerequisite for their metastatic spread. Inducing anoikis in metastatic cancer cells is therefore a promising therapeutic approach. The vacuolar-ATPase (V-ATPase), a proton pump located at the membrane of acidic organelles, has recently come to focus as an antimetastatic cancer target. As V-ATPase inhibitors have shown to prevent invasion of tumor cells and are able to induce apoptosis, we proposed that VATPase inhibition induces anoikis-related pathways in invasive cancer cells. We used the V-ATPase inhibitor archazolid to investigate the mechanism of anoikis induction in various metastatic cancer cells (T24, MDA-MB-231, 4T1, 5637) in vitro. Anoikis induction by archazolid was characterized by decreased c-FLIP expression and caspase-8 activation as well as reduction of active integrin-b1 and an early increase of the proapoptotic protein BIM. However, we observed that archazolid also induces mechanisms opposing anoikis such as degradation of BIM mediated by extracellular signal-regulated kinase (ERK), Akt and Src kinases at later time points and induction of reactive oxygen species. Still, intravenous injection of archazolid-treated 4T1-Luc2 mouse breast cancer cells resulted in reduced metastasis in mouse lungs. Thus, V-ATPase inhibition is not only an interesting option to reduce cancer metastasis, but also to better understand anoikis resistance and to find choices to fight against it. Mol Cancer Ther; 13(4); 926-37. Ó2014 AACR.

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

“…V‐ATPase inhibition has been shown to result in increased reactive oxygen species (ROS) in cancer cells75, 76, 77 and HIF1α upregulation 74. Furthermore, V‐ATPase inhibition induces caspase‐dependent apoptosis in invasive tumor cells via the mitochondrial pathways 74, 78.…”

Evolving Strategies for Therapeutically Targeting Cancer Stem Cells

“…Normal cells undergo an apoptotic process called anoikis, after the loss of contact with the extracellular matrix or neighboring cells (Fofaria & Srivastava, 2015;Schempp et al, 2014;Simpson, Anyiwe, & Schimmer, 2008). Anoikis resistance is essential for cancer cells to endure the process of dissemination via the circulatory and lymphatic systems, after detachment from primary sites (Kim, Koo, Sung, Yun, & Kim, 2012).…”

Selective upregulation of TNFα expression in classically-activated human monocyte-derived macrophages (M1) through pharmacological interference with V-ATPase

“…Archazolid has been intensively investigated as anti-tumoral agent that induced apoptosis of cancer cells and reduced migration of invasive tumor cells in vitro, and decreased metastatic dissemination of breast tumors in vivo [18][19][20]. In various highly invasive tumor cell lines and leukemic cells, archazolid led to apoptosis due to activation of the hypoxia-inducible factor-1α (HIF1α) [18,21], and to anoikis induction [22]. Thus, archazolid represents a promising candidate for direct targeting of tumor cells via V-ATPase inhibition.…”