Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival

Abstract

During metastatic progression, circulating cancer cells become lodged within the microvasculature of end-organs, where a majority die from mechanical deformation. Though this phenomenon was first described over a half-century ago, the mechanisms enabling certain cells to survive this metastasis-suppressive barrier remain unknown. By applying whole-transcriptome RNA-sequencing (RNA-seq) technology to isogenic cancer cells of differing metastatic capacity, we identified a mutation encoding a truncated form of the pannexin-1 (PANX1) channel, PANX1 1–89, as recurrently enriched in highly metastatic breast cancer cells. PANX1 1–89 functions to permit metastatic cell survival during traumatic deformation in the microvasculature by augmenting ATP release from mechanosensitive PANX1 channels activated by membrane stretch. PANX1-mediated ATP release acts as an autocrine suppressor of deformation-induced apoptosis via P2y-purinergic receptors. Finally, small-molecule therapeutic inhibition of PANX1 channels is found to reduce the efficiency of breast cancer metastasis. These data suggest a molecular basis for metastatic cell survival upon microvasculature-induced biomechanical trauma.

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…In addition to their role in nucleotide release from apoptotic cells, the pannexin channels are also involved in regulating the integrity of the dying cells, 63 regulation of vascular constriction via nucleotides released by non-apoptotic mechanisms, 64 and cancer cell migration. 65 Owing to the ubiquitous expression 66 and vast regulatory mechanisms of Panx1 activation, 61,67 novel cell-type-specific knock-out and transgenic mice affecting apoptosis-specific activation may be necessary to understand its involvement during cell clearance in vivo. Numerous knock-out studies have been performed on other proteins involved in different aspects of these attraction signals.…”

A new perspective of mechanosensitive pannexin-1 channels in cancer metastasis: clues for the treatment of other stress-induced diseases

“…Additionally, carbenoxolone (CBX), a Panx-1 inhibitor, was proved to reduce the efficiency of breast cancer metastasis. These results suggested that Panx-1 is one of the molecular bases for metastatic cell survival in microvasculature-induced biomechanical trauma [1]. In 2000, three members of pannexins, including Panx-1, Panx-2, and Panx-3, have been found to be new members of gap-junctions' family [2].…”

“…However, the roles of ATP in cancer cell death or survival are controversial. Furlow et al [1] found that ATP release from Panx-1 channels activated P2Y-purinergic receptors then promoted cancer cell survival. Moreover, metastasis cell viability was markedly reduced after exposure to the ATP hydrolase [19].…”

“…However, cancer cells can survive from mechanical deformation by unknown mechanisms. Recently, Furlow et al [1] identified a mutation truncated form of pannexin-1 (Panx-1), PANX1 , which was significantly enriched in highly metastatic cancer cells. PANX1 augmented Panx-1 channel-mediated adenosine triphosphate (ATP) release and enhanced the efficiency of metastasis by promoting metastatic breast cancer cells survival during physical deformation.…”

“…The next question is whether mutations of Panx-1 exist in these diseases? Furlow et al [1] identified a mutation encoding a truncated form of the Panx-1 channel, PANX1 , as recurrently enriched in highly metastatic breast cancer cells. PANX1 functions to permit metastatic cell survival during traumatic deformation in the microvasculature by augmenting ATP release from mechanosensitive Panx-1 channels activated by membrane stretch.…”