V-ATPase inhibition regulates anoikis resistance and metastasis of cancer cells.
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 V-ATPase 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-β1 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.
Authors' Affiliations: Department of Pharmacy, Pharmaceutical Biology and Department of Pharmacy, Pharmaceutical Biotechnology, University of Munich, Munich; and Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
Christina M
CM
Schempp
Karin
K
von Schwarzenberg
Laura
L
Schreiner
Rebekka
R
Kubisch
Rolf
R
Müller
Ernst
E
Wagner
Angelika M
AM
Vollmar
D000818:Animals; D023102:Anoikis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000556:secondary; D018942:Macrolides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
D018942:Macrolides; D013844:Thiazoles; C529652:archazolide A