Vacuolar-ATPase Inhibition Blocks Iron Metabolism to Mediate Therapeutic Effects in Breast Cancer

Abstract

Generalized strategies to improve breast cancer treatment remain of interest to develop. In this study, we offer preclinical evidence of an important metabolic mechanism underlying the antitumor activity of inhibitors of the vacuolar-type ATPase (V-ATPase), a heteromultimeric proton pump. Specifically, our investigations in the 4T1 model of metastatic breast cancer of the V-ATPase inhibitor archazolid suggested that its ability to trigger metabolic stress and apoptosis associated with tumor growth inhibition related to an interference with hypoxia-inducible factor-1a signaling pathways and iron metabolism. As a consequence of disturbed iron metabolism, archazolid caused S-phase arrest, double-stranded DNA breaks, and p53 stabilization, leading to apoptosis. Our findings link V-ATPase to cell-cycle progression and DNA synthesis in cancer cells, and highlight the basis for the clinical exploration of V-ATPase as a potentially generalizable therapy for breast cancer.

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

“…It was therefore suggested that V‐ATPase induced cytotoxicity may primarily be due to disturbed iron receptor recycling, impairing the iron metabolism of tumor cells 79. Consistent with this, the expression of genes responsive to a decrease in iron was greatly increased in response to V‐ATPase inhibition.…”

“…Furthermore, V‐ATPase inhibition induces caspase‐dependent apoptosis in invasive tumor cells via the mitochondrial pathways 74, 78. Archazolid was also shown to induce cell cycle arrest in MDA‐MB‐231 cells and double‐strand breaks in all cell lines investigated 79. This evidence indicates that V‐ATPase inhibition can induce a cellular stress response, autophagy, and eventually apoptosis in tumor cells.…”

V-ATPase inhibition increases cancer cell stiffness and blocks membrane related Ras signaling - a new option for HCC therapy

“…The fact that increased cell compliance correlates with cancer cell malignancy [17] and the fact that V-ATPase regulates cholesterol metabolism [13, 14, 21] resulted in the working hypothesis that modulation of V-ATPase by archazolid A might influence cell deformability. Here, we took advantage of a new microfluidic-based technique called real-time deformability cytometry (RT-DC), which allows the measurement of cell deformation while cells pass through a narrow constriction with a rate of 100 cells/sec [22].…”

Recent Insights into the Structure, Regulation, and Function of the V-ATPases

“…One study has found that intracellular acidosis caused by V-ATPase inhibition in breast cancer cells stabilizes expression of the pro-apoptotic protein Bnip3, resulting in cell death [95]. It has also recently been demonstrated that treatment of breast cancer cells with the V-ATPase inhibitor archazolid disrupts internalization of the transferrin receptor, leading to iron deprivation and subsequent apoptosis [98]. Further work is needed to better elucidate how the pump is involved in cell growth and survival.…”