P2X7 receptor stimulates breast cancer cell invasion and migration via the AKT pathway

Xia,Jiyi; Yu,Xiaolan; Tang,Li; Li,Gang; He,Tao

doi:10.3892/or.2015.3979

P2X7 receptor stimulates breast cancer cell invasion and migration via the AKT pathway

Authors:
- Jiyi Xia
- Xiaolan Yu
- Li Tang
- Gang Li
- Tao He
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Affiliations: Research Center for Drug and Functional Food, Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China, Department of Obstetrics and Gynecology, The Affiliated TCM Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China, Experimental Medicine Center, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China, Department of Pediatrics, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China, Department of Biochemistry, Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China
Published online on: May 13, 2015 https://doi.org/10.3892/or.2015.3979
Pages: 103-110

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Abstract

Purinergic signaling has been implicated in the regulation of many cellular processes. A high concentration of ATP has been observed in the tumor microenvironment, suggesting a possible role of extracellular ATP in tumor progression. The P2X7 receptor, which belongs to the ligand-gated ion channel receptor family, is involved in tumor development and metastasis. In the present study, we found that extracellular ATP stimulated the invasion and migration of human T47D breast cancer cells, in a dose-dependent manner. BzATP (ATP analogue), but not ADP, also promoted invasion and migration. We further found that the P2X7 receptor was highly expressed in the T47D cells. After knockdown of the P2X7 receptor, ATP-stimulated invasion and migration were markedly inhibited. Moreover, activation of the P2X7 receptor by ATP downregulated the protein level of E-cadherin and upregulated the production of MMP-13. In addition, ATP time-dependently induced the activation of AKT via the P2X7 receptor, and the AKT pathway was required for the ATP-mediated invasion and migration. Taken together, our results revealed that activation of the P2X7 receptor by ATP promotes breast cancer cell invasion and migration, possibly via activation of the AKT pathway and regulation of E-cadherin and MMP-13 expression. Therefore, the P2X7 receptor may be a useful therapeutic target for the treatment of breast cancer.

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1	Burnstock G: Purinergic signalling: Pathophysiology and therapeutic potential. Keio J Med. 62:63–73. 2013. View Article : Google Scholar : PubMed/NCBI
2	Braganhol E, Wink MR, Lenz G and Battastini AM: Purinergic signaling in glioma progression. Adv Exp Med Biol. 986:81–102. 2013. View Article : Google Scholar
3	Burnstock G: Introduction: P2 receptors. Curr Top Med Chem. 4:793–803. 2004. View Article : Google Scholar : PubMed/NCBI
4	Solini A, Cuccato S, Ferrari D, Santini E, Gulinelli S, Callegari MG, Dardano A, Faviana P, Madec S, Di Virgilio F, et al: Increased P2X7 receptor expression and function in thyroid papillary cancer: A new potential marker of the disease? Endocrinology. 149:389–396. 2008. View Article : Google Scholar
5	Zhang XJ, Zheng GG, Ma XT, Yang YH, Li G, Rao Q, Nie K and Wu KF: Expression of P2X7 in human hematopoietic cell lines and leukemia patients. Leuk Res. 28:1313–1322. 2004. View Article : Google Scholar : PubMed/NCBI
6	Li X, Qi X, Zhou L, Catera D, Rote NS, Potashkin J, Abdul-Karim FW and Gorodeski GI: Decreased expression of P2X7 in endometrial epithelial pre-cancerous and cancer cells. Gynecol Oncol. 106:233–243. 2007. View Article : Google Scholar : PubMed/NCBI
7	Li X, Zhou L, Feng YH, Abdul-Karim FW and Gorodeski GI: The P2X7 receptor: A novel biomarker of uterine epithelial cancers. Cancer Epidemiol Biomarkers Prev. 15:1906–1913. 2006. View Article : Google Scholar : PubMed/NCBI
8	DeSantis C, Ma J, Bryan L and Jemal A: Breast cancer statistics, 2013. CA Cancer J Clin. 64:52–62. 2014. View Article : Google Scholar
9	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
10	Jelassi B, Chantôme A, Alcaraz-Pérez F, Baroja-Mazo A, Cayuela ML, Pelegrin P, Surprenant A and Roger S: P2X(7) receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness. Oncogene. 30:2108–2122. 2011. View Article : Google Scholar : PubMed/NCBI
11	Sun SH: Roles of P2X7 receptor in glial and neuroblastoma cells: The therapeutic potential of P2X7 receptor antagonists. Mol Neurobiol. 41:351–355. 2010. View Article : Google Scholar : PubMed/NCBI
12	Canel M, Serrels A, Frame MC and Brunton VG: E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci. 126:393–401. 2013. View Article : Google Scholar : PubMed/NCBI
13	Sheng S, Qiao M and Pardee AB: Metastasis and AKT activation. J Cell Physiol. 218:451–454. 2009. View Article : Google Scholar
14	Yang G, Zhang S, Zhang Y, Zhou Q, Peng S, Zhang T, Yang C, Zhu Z and Zhang F: The inhibitory effects of extracellular ATP on the growth of nasopharyngeal carcinoma cells via P2Y2 receptor and osteopontin. J Exp Clin Cancer Res. 33:532014. View Article : Google Scholar : PubMed/NCBI
15	Li WH, Qiu Y, Zhang HQ, Liu Y, You JF, Tian XX and Fang WG: P2Y2 receptor promotes cell invasion and metastasis in prostate cancer cells. Br J Cancer. 109:1666–1675. 2013. View Article : Google Scholar : PubMed/NCBI
16	Shi K, Queiroz KC, Stap J, Richel DJ and Spek CA: Protease-activated receptor-2 induces migration of pancreatic cancer cells in an extracellular ATP-dependent manner. J Thromb Haemost. 11:1892–1902. 2013.PubMed/NCBI
17	Gu LQ, Li FY, Zhao L, Liu Y, Chu Q, Zang XX, Liu JM, Ning G and Zhao YJ: Association of XIAP and P2X7 receptor expression with lymph node metastasis in papillary thyroid carcinoma. Endocrine. 38:276–282. 2010. View Article : Google Scholar : PubMed/NCBI
18	Kwon JH, Nam ES, Shin HS, Cho SJ, Park HR and Kwon MJ: P2X7 receptor expression in coexistence of papillary thyroid carcinoma with Hashimoto’s thyroiditis. Korean J Pathol. 48:30–35. 2014. View Article : Google Scholar : PubMed/NCBI
19	Adinolfi E, Raffaghello L, Giuliani AL, Cavazzini L, Capece M, Chiozzi P, Bianchi G, Kroemer G, Pistoia V and Di Virgilio F: Expression of P2X7 receptor increases in vivo tumor growth. Cancer Res. 72:2957–2969. 2012. View Article : Google Scholar : PubMed/NCBI
20	Hattori F, Ohshima Y, Seki S, Tsukimoto M, Sato M, Takenouchi T, Suzuki A, Takai E, Kitani H, Harada H, et al: Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7. Eur J Pharmacol. 695:20–26. 2012. View Article : Google Scholar : PubMed/NCBI
21	Takai E, Tsukimoto M, Harada H and Kojima S: Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells. Purinergic Signal. 10:487–497. 2014. View Article : Google Scholar : PubMed/NCBI
22	Wang Y and Zhou BP: Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chin J Cancer. 30:603–611. 2011. View Article : Google Scholar : PubMed/NCBI
23	Davis FM, Kenny PA, Soo ET, van Denderen BJ, Thompson EW, Cabot PJ, Parat MO, Roberts-Thomson SJ and Monteith GR: Remodeling of purinergic receptor-mediated Ca²⁺ signaling as a consequence of EGF-induced epithelial-mesenchymal transition in breast cancer cells. PLoS One. 6:e234642011. View Article : Google Scholar
24	Paredes J, Figueiredo J, Albergaria A, Oliveira P, Carvalho J, Ribeiro AS, Caldeira J, Costa AM, Simões-Correia J, Oliveira MJ, et al: Epithelial E- and P-cadherins: Role and clinical significance in cancer. Biochim Biophys Acta. 1826:297–311. 2012.PubMed/NCBI
25	Morrison C, Mancini S, Cipollone J, Kappelhoff R, Roskelley C and Overall C: Microarray and proteomic analysis of breast cancer cell and osteoblast co-cultures: Role of osteoblast matrix metalloproteinase (MMP)-13 in bone metastasis. J Biol Chem. 286:34271–34285. 2011. View Article : Google Scholar : PubMed/NCBI
26	Pivetta E, Scapolan M, Pecolo M, Wassermann B, Abu-Rumeileh I, Balestreri L, Borsatti E, Tripodo C, Colombatti A and Spessotto P: MMP-13 stimulates osteoclast differentiation and activation in tumour breast bone metastases. Breast Cancer Res. 13:R1052011. View Article : Google Scholar : PubMed/NCBI
27	Zhang Y, Gong LH, Zhang HQ, Du Q, You JF, Tian XX and Fang WG: Extracellular ATP enhances in vitro invasion of prostate cancer cells by activating Rho GTPase and upregulating MMPs expression. Cancer Lett. 293:189–197. 2010. View Article : Google Scholar : PubMed/NCBI
28	Vázquez-Cuevas FG, Martínez-Ramírez AS, Robles-Martínez L, Garay E, García-Carrancá A, Pérez-Montiel D, Castañeda-García C and Arellano RO: Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells. J Cell Biochem. 115:1955–1966. 2014.PubMed/NCBI
29	Bian S, Sun X, Bai A, Zhang C, Li L, Enjyoji K, Junger WG, Robson SC and Wu Y: P2X7 integrates PI3K/AKT and AMPK-PRAS40-mTOR signaling pathways to mediate tumor cell death. PLoS One. 8:e601842013. View Article : Google Scholar : PubMed/NCBI
30	Lauring J, Park BH and Wolff AC: The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J Natl Compr Canc Netw. 11:670–678. 2013.PubMed/NCBI