In its metastatic form melanoma is one of the most deadly cancers. Despite increasing prevalence, treatment of melanoma is still challenging. Taking advantage of a murine model of melanoma, we recently demonstrated that intratumoral injection of a P2X7 receptor antagonist is effective in reducing tumor growth and vessels formation (1). P2X7 receptor (P2RX7) is an ATP-gated ion channel that has been involved both in oncogenesis (2) and anti-tumoral host response (3). In order to extend our understanding of P2RX7 role in melanoma biology, we investigated the effect of its silencing in B16 murine melanoma cell line. B16 were transfected with two different short-harpinRNA constructs directed against P2RX7. The silenced clones, if compared to the control, showed reduced P2RX7 activity and lower proliferation rate, even in presence of growth factors. Interestingly, in contrast microscopy, B16 P2RX7 silenced clones displayed melanocyte-like features, such as enhanced formation of cellular projections, thus suggesting an involvement of the receptor in de-differentiation of pigment-producing cells of the skin. Compared to P2RX7 positive control, receptor down-modulation significantly reduced in vivo tumor growth and dimensions in subcutaneously injected in C57Black/6 mice. A similar effect was obtained by intraperitoneal administration of different receptor antagonists. Surprisingly, when injected in C57Black/6 P2X7-/- mice, B16 cells gave rise to bigger tumoral masses suggesting an important role for P2RX7 also in modulating anti-tumoral host response. However, if P2X7-/- mice were injected with P2RX7 silenced clones, melanoma dimensions were greatly reduced, in accordance with data obtained by systemic receptor inhibition. Taken together, our results corroborate the hypothesis of P2RX7 receptor as therapeutic target in melanoma. 1. Adinolfi E et al. Cancer Res. 2012, 72:2957-69. 2. Di Virgilio F Cancer Res. 2012, 72:5441-7. 3. Ghiringhelli F et al. Nat Med. 2009, 15:1170-8.
P2X7 contemporarily impacts melanoma growth and anti-melanoma defense
CAPECE, Marina;FRANCESCHINI, Alessia;ABELLI, Luigi;DI VIRGILIO, Francesco;ADINOLFI, Elena
2013
Abstract
In its metastatic form melanoma is one of the most deadly cancers. Despite increasing prevalence, treatment of melanoma is still challenging. Taking advantage of a murine model of melanoma, we recently demonstrated that intratumoral injection of a P2X7 receptor antagonist is effective in reducing tumor growth and vessels formation (1). P2X7 receptor (P2RX7) is an ATP-gated ion channel that has been involved both in oncogenesis (2) and anti-tumoral host response (3). In order to extend our understanding of P2RX7 role in melanoma biology, we investigated the effect of its silencing in B16 murine melanoma cell line. B16 were transfected with two different short-harpinRNA constructs directed against P2RX7. The silenced clones, if compared to the control, showed reduced P2RX7 activity and lower proliferation rate, even in presence of growth factors. Interestingly, in contrast microscopy, B16 P2RX7 silenced clones displayed melanocyte-like features, such as enhanced formation of cellular projections, thus suggesting an involvement of the receptor in de-differentiation of pigment-producing cells of the skin. Compared to P2RX7 positive control, receptor down-modulation significantly reduced in vivo tumor growth and dimensions in subcutaneously injected in C57Black/6 mice. A similar effect was obtained by intraperitoneal administration of different receptor antagonists. Surprisingly, when injected in C57Black/6 P2X7-/- mice, B16 cells gave rise to bigger tumoral masses suggesting an important role for P2RX7 also in modulating anti-tumoral host response. However, if P2X7-/- mice were injected with P2RX7 silenced clones, melanoma dimensions were greatly reduced, in accordance with data obtained by systemic receptor inhibition. Taken together, our results corroborate the hypothesis of P2RX7 receptor as therapeutic target in melanoma. 1. Adinolfi E et al. Cancer Res. 2012, 72:2957-69. 2. Di Virgilio F Cancer Res. 2012, 72:5441-7. 3. Ghiringhelli F et al. Nat Med. 2009, 15:1170-8.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
