P2X7/<scp>PANX</scp>1 as a new target for melanoma?

Mantel, Alon; Harvey, Valérie

doi:10.1111/exd.12633

Cited by 7 publications

(6 citation statements)

References 8 publications

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“…54 We also observed that the eATP-driven increase in cell migration is significantly decreased following the inhibition of the purinergic receptors, more specifically, P2RX7 in line with a previous study in lung cancer cells. 45 P2RX7 is an ATP-gated ion channel also expressed in melanoma cells, 55 with the potential to mediate endocytosis. Interestingly, P2RX7 has a wellestablished role in facilitating cancer migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

“…6,8,39,59 ) but potentially also its autocrine/paracrine promigratory and pro-invasion effects exerted via eATP-P2RX7 interaction. 15,19,55 However, further in vivo studies need to be performed to evaluate the effects of the inhibition of PLX-resistant melanoma cell-associated autophagy on their metastatic potential, because eATP and its degradation products influence key features of the tumor microenvironment, including immuno-surveillance mechanisms and therapeutic responses. 40,63 Irrespective of these interesting conjectures, our study unravels a pro-invasive role for melanoma cell-associated autophagy following both in vitro acquired, as well as primary resistance to, PLX, whereby the increased autophagy promotes through the trafficking and extracellular secretion of ATP key hallmarks of melanoma's aggressive phenotype.…”

Section: Discussionmentioning

confidence: 99%

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An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF^V600E inhibitor-resistant metastatic melanoma cells

et al. 2017

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The ingrained capacity of melanoma cells to rapidly evolve toward an aggressive phenotype is manifested by their increased ability to develop drug-resistance, evident in the case of vemurafenib, a therapeutic-agent targeting BRAF. Previous studies indicated a tight correlation between heightened melanoma-associated macroautophagy/autophagy and acquired Vemurafenib resistance. However, how this vesicular trafficking pathway supports Vemurafenib resistance remains unclear. Here, using isogenic human and murine melanoma cell lines of Vemurafenib-resistant and patient-derived melanoma cells with primary resistance to the BRAF inhibitor, we found that the enhanced migration and invasion of the resistant melanoma cells correlated with an enhanced autophagic capacity and autophagosome-mediated secretion of ATP. Extracellular ATP (eATP) was instrumental for the invasive phenotype and the expansion of a subset of Vemurafenib-resistant melanoma cells. Compromising the heightened autophagy in these BRAF inhibitor-resistant melanoma cells through the knockdown of different autophagy genes (ATG5, ATG7, ULK1), reduced their invasive and eATP-secreting capacity. Furthermore, eATP promoted the aggressive nature of the BRAF inhibitor-resistant melanoma cells by signaling through the purinergic receptor P2RX7. This autophagy-propelled eATP-dependent autocrine-paracrine pathway supported the maintenance and expansion of a drug-resistant melanoma phenotype. In conclusion, we have identified an autophagy-driven response that relies on the secretion of ATP to drive P2RX7-based migration and expansion of the Vemurafenib-resistant phenotype. This emphasizes the potential of targeting autophagy in the treatment and management of metastatic melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF^V600E inhibitor-resistant metastatic melanoma cells

et al. 2017

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“…ATP concentration at normal state is usually at nanomolar range, but goes up to milimolar range when exposed to inflammation, tissue damage, or other pathological conditions (Aymeric et al, 2010;Burnstock et al, 2012a;Sáez et al, 2017;Wilhelm et al, 2010). ATP is a well-known anti-tumor treatment for melanoma because high ATP concentrations limit skin tumor cell proliferation and differentiation through P2Y1, P2Y2, and P2Y5 receptors and induce apoptotic cell death through P2X7 receptors (Burnstock and Verkhratsky, 2010;Mantel and Harvey, 2015;White et al, 2009). In our study, UVB radiation can stimulate ATP extracellular release from both keratinocytes and melanocytes, consistent with preceding studies (Inoue et al, 2007;Takai et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of ATP-P2X7 Axis in UV-Induced Melanogenesis

Lee

Kim

Ahn

et al. 2019

Journal of Investigative Dermatology

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Purinergic signaling participates in skin physiology and pathology, such as hair growth, wound healing, inflammation, pain, and skin cancer. However, few studies have investigated the involvement of purinergic signaling in skin pigmentation. This study demonstrated that extracellular adenosine 5 0-triphosphate (ATP) released from keratinocytes by UVB radiation promotes melanin production in primary human epidermal melanocytes and ex vivo skin cultures. Intracellular calcium ion and protein kinase C/CREB signaling contributed to ATP-mediated melanogenesis. Also, P2X7 receptor was proven to play a pivotal role in ATPmediated melanogenesis because P2X7 receptor blockade abrogated ATP-induced melanin production. In addition, MNT1 cells with P2X7 receptor knockout using CRISPR/Cas9 system did not show any increase in MITF expression when co-cultured with UV-irradiated keratinocytes compared to MNT1 cells with intact P2X7 receptor, which showed increased expression of MITF. In conclusion, our results indicate that the extracellular ATP-P2X7 signaling axis is an adjunctive mechanism in UV-induced melanogenesis. Furthermore, ATP-induced purinergic signaling in melanocytes may alter skin pigmentation.

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“…Recently, two articles have highlighted the link between inflammation and melanoma, proposing the involvement of the Panx1/P2X7 complex as a key regulator [ 33 , 173 ]. The Panx1/P2X7 complex has been shown to activate the NLRP3 inflammasome and participate in the release of IL-1β in vitro [ 34 , 174 , 175 ].…”

Section: Panx1 In Melanoma and Links To Inflammationmentioning

confidence: 99%

“…Other mutations in the melanoma cell alter normal growth cycle feedback, and with this inflammasome activation, may continue to proliferate without control [ 33 ]. A caveat to this model is the possibility that high levels of ATP may do the opposite and reduce growth and tumorigenicity in cancer cells as pointed out by Mantel and Harvey [ 173 ]. Additionally, this same pathway involving the NLRP3 inflammasome, can result in the activation of cell death and pyroptosis, which would have the opposite effect.…”

Section: Panx1 In Melanoma and Links To Inflammationmentioning

confidence: 99%

Connexin and pannexin channels in cancer

Jiang

Peñuela

2016

BMC Cell Biol

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Communication among cells via direct cell-cell contact by connexin gap junctions, or between cell and extracellular environment via pannexin channels or connexin hemichannels, is a key factor in cell function and tissue homeostasis. Upon malignant transformation in different cancer types, the dysregulation of these connexin and pannexin channels and their effect in cellular communication, can either enhance or suppress tumorigenesis and metastasis. In this review, we will highlight the latest reports on the role of the well characterized connexin family and its ability to form gap junctions and hemichannels in cancer. We will also introduce the more recently discovered family of pannexin channels and our current knowledge about their involvement in cancer progression.

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P2X7/PANX1 as a new target for melanoma?

Cited by 7 publications

References 8 publications

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF^V600E inhibitor-resistant metastatic melanoma cells

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF^V600E inhibitor-resistant metastatic melanoma cells

Critical Role of ATP-P2X7 Axis in UV-Induced Melanogenesis

Connexin and pannexin channels in cancer

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P2X7/PANX1 as a new target for melanoma?

Cited by 7 publications

References 8 publications

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells

Critical Role of ATP-P2X7 Axis in UV-Induced Melanogenesis

Connexin and pannexin channels in cancer

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Product

Resources

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An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF^V600E inhibitor-resistant metastatic melanoma cells

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF^V600E inhibitor-resistant metastatic melanoma cells