Vacuolar-ATPase inhibition blocks iron metabolism to mediate therapeutic effects in breast cancer

Lina S. Schneider, Karin Von Schwarzenberg, Thorsten Lehr, Melanie Ulrich, Rebekka Kubisch-Dohmen, Johanna Liebl, Dirk Trauner, Dirk Menche, Angelika M. Vollmar

Research output: Contribution to journalArticle

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-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.

Original languageEnglish (US)
Pages (from-to)2863-2874
Number of pages12
JournalCancer Research
Volume75
Issue number14
DOIs
StatePublished - Jul 15 2015

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Vacuolar Proton-Translocating ATPases
Therapeutic Uses
Iron
Breast Neoplasms
Apoptosis
Hypoxia-Inducible Factor 1
Proton Pumps
Physiological Stress
Double-Stranded DNA Breaks
S Phase
Neoplasms
Cell Cycle
DNA
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Schneider, L. S., Von Schwarzenberg, K., Lehr, T., Ulrich, M., Kubisch-Dohmen, R., Liebl, J., ... Vollmar, A. M. (2015). Vacuolar-ATPase inhibition blocks iron metabolism to mediate therapeutic effects in breast cancer. Cancer Research, 75(14), 2863-2874. https://doi.org/10.1158/0008-5472.CAN-14-2097

Vacuolar-ATPase inhibition blocks iron metabolism to mediate therapeutic effects in breast cancer. / Schneider, Lina S.; Von Schwarzenberg, Karin; Lehr, Thorsten; Ulrich, Melanie; Kubisch-Dohmen, Rebekka; Liebl, Johanna; Trauner, Dirk; Menche, Dirk; Vollmar, Angelika M.

In: Cancer Research, Vol. 75, No. 14, 15.07.2015, p. 2863-2874.

Research output: Contribution to journalArticle

Schneider, LS, Von Schwarzenberg, K, Lehr, T, Ulrich, M, Kubisch-Dohmen, R, Liebl, J, Trauner, D, Menche, D & Vollmar, AM 2015, 'Vacuolar-ATPase inhibition blocks iron metabolism to mediate therapeutic effects in breast cancer', Cancer Research, vol. 75, no. 14, pp. 2863-2874. https://doi.org/10.1158/0008-5472.CAN-14-2097
Schneider LS, Von Schwarzenberg K, Lehr T, Ulrich M, Kubisch-Dohmen R, Liebl J et al. Vacuolar-ATPase inhibition blocks iron metabolism to mediate therapeutic effects in breast cancer. Cancer Research. 2015 Jul 15;75(14):2863-2874. https://doi.org/10.1158/0008-5472.CAN-14-2097
Schneider, Lina S. ; Von Schwarzenberg, Karin ; Lehr, Thorsten ; Ulrich, Melanie ; Kubisch-Dohmen, Rebekka ; Liebl, Johanna ; Trauner, Dirk ; Menche, Dirk ; Vollmar, Angelika M. / Vacuolar-ATPase inhibition blocks iron metabolism to mediate therapeutic effects in breast cancer. In: Cancer Research. 2015 ; Vol. 75, No. 14. pp. 2863-2874.
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