Editors' ChoiceCancer

Increasing ATP release to increase metastasis

Sci. Signal.  14 Jul 2015:
Vol. 8, Issue 385, pp. ec188
DOI: 10.1126/scisignal.aac9985

Cancer cells that metastasize from the primary tumor must survive mechanical stresses in the microvasculature. Furlow et al. identified mutations that were more frequent in metastatic human CN-LM1A and MDA-LM2 breast cancer cells than in their less metastatic parental cell lines. One of these mutations generated a truncated form (PANX11-89) of the mechanosensitive channel pannexin-1, which releases ATP from cells. Inhibition of PANX1 reduced extracellular ATP release from CN-LM1A and MDA-LM2 cells. PANX11-89 interacted with full-length PANX1 in cells expressing both forms. Overexpression of the truncated form increased extracellular ATP release from HEK293T cells coexpressing full-length PANX1 and from various human breast cancer cells with endogenous full-length PANX1, but not in cells lacking full-length PANX1. CN-LM1A and MDA-LM2 cells injected into mice released ATP, as detected by the activity of a reporter construct with an extracellular luciferase domain expressed in these cells. Preincubation of these cells with PANX1 inhibitors before tail vein injection increased cell death in the microvasculature and reduced lung colonization. Conversely, expression of PANX1-89 in cancer cells that do not have this mutant increased intravascular survival and metastasis of these cells when orthotopically implanted or injected into mice. Hypotonic cell swelling induces stretching of the plasma membrane and activates PANX1 channels. The authors used hypotonic swelling to mimic the elongation that was detected in metastasizing cancer cells in the microvasculature. When subjected to hypotonic cell swelling, CN-LM1A and MDA-LM2 cells showed increased ATP release through PANX1 and more of these cells survived hypotonic cell swelling than the parental cell lines. PANX1 inhibitors or an antagonist of P2Y purinergic receptors blocked survival and ATP release in cells subjected to hypotonic cell swelling, suggesting that the ATP released through PANX1 acted in a cell-autonomous manner. The PANX1 inhibitor carbenoxolone is currently in clinical use, and metastasis was decreased in mice pretreated with carbenoxolone at different times before they were injected with MDA-LM2 or CN-LM1A cells.

P. W. Furlow, S. Zhang, T. D. Soong, N. Halberg, H. Goodarzi, C. Mangrum, Y. G. Wu, O. Elemento, S. F. Tavazoie, Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival. Nat. Cell Biol. 17, 943–952 (2015). [PubMed]