TY - JOUR
T1 - Vacuolar-ATPase inhibition blocks iron metabolism to mediate therapeutic effects in breast cancer
AU - Schneider, Lina S.
AU - Von Schwarzenberg, Karin
AU - Lehr, Thorsten
AU - Ulrich, Melanie
AU - Kubisch-Dohmen, Rebekka
AU - Liebl, Johanna
AU - Trauner, Dirk
AU - Menche, Dirk
AU - Vollmar, Angelika M.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/7/15
Y1 - 2015/7/15
N2 - 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-1α 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.
AB - 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-1α 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.
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U2 - 10.1158/0008-5472.CAN-14-2097
DO - 10.1158/0008-5472.CAN-14-2097
M3 - Article
C2 - 26018087
AN - SCOPUS:84942164064
SN - 0008-5472
VL - 75
SP - 2863
EP - 2874
JO - Cancer Research
JF - Cancer Research
IS - 14
ER -