Abstract
The tumor microenvironment plays a major role in the ability of the tumor cells to undergo metastasis. A major player of tumors gaining metastatic property is the inflammatory protein, cyclooxygenase 2 (COX-2). Several tumors show upregulation of this protein, which has been implicated in mediating metastasis in various cancer types such as of colon, breast and lung. In this report, we show that the concentration of extracellular ATP (eATP) is increased in response to cell death mediated by chemotherapeutic agents such as doxorubicin. By using three different cell-lines—HeLa (cervical), IMR-32 (neuronal) and MCF-7 (breast)—we show that this eATP goes on to act on purinergic (P2) receptors. Among the various P2 receptors expressed in these cells we identified P2X7, in IMR-32 and MCF-7 cells, and P2Y12, in HeLa cells, as important in modulating cell migration and invasion. Downstream of the P2 receptor activation, both p42/44 mitogen-activated protein kinase (MAPK) and the p38 MAPK are activated in these cells. These result in an increase in the expression of COX-2 mRNA and protein. We also observe an increase in the activity of matrix metalloproteinase 2 (MMP-2) enzyme in these cells. Blocking the P2 receptors not only blocks migration and invasion, but also COX-2 synthesis and MMP-2 activity. Our results show the link between purinergic receptors and COX-2 expression. Increased levels of ATP in the tumor microenvironment, therefore, leads to increased COX-2 expression, which, in turn, affords migratory and invasive properties to the tumor. This provides P2 receptor-based anti-inflammatory drugs (PBAIDs) a potential opportunity to be explored as cancer therapeutics.
Highlights
The incidences of cancer detection are on the rise with more than 9.6 million deaths in 2018 alone (Bray et al, 2018)
We have hypothesized that extracellular ATP (eATP), which is found at very high concentrations in the tumor microenvironment, is responsible for eATP Modulates cyclooxygenase 2 (COX-2) in Tumour the increased expression of COX-2 which in turn affords the cells with migratory and invasive properties turning the tumor into a metastatic one
While HeLa and MCF-7 are frequently used in cancer research, IMR-32 was included in this study because of it being a neuroblastoma derived from a metastatic site in the abdomen and carrying two types of cells—a predominant smaller neuroblast-like cells and larger hyaline fibroblast cells (Tumilowicz et al, 1970)
Summary
The incidences of cancer detection are on the rise with more than 9.6 million deaths in 2018 alone (Bray et al, 2018). Its role in cancer has been observed, especially related to tumors acquiring metastatic potential and chemotherapy resistance (Ferrandina et al, 2002; Li et al, 2002) Many cancer types such as leukemia, breast cancer, pancreatic cancer, lung cancer and lymphomas show overexpression of COX-2 (Nakanishi et al, 2001; Ristimaki et al, 2002; Wun et al, 2004; Secchiero et al, 2005). This increase in COX-2 has been shown to enhance tumor progression through increased apoptosis resistance and increased metastatic properties (Choi et al, 2005; Singh et al, 2007; Karavitis and Zhang, 2013). The nuclear factor κB (NF-κB) pathway has been implicated in the increased expression of COX2 in cancer cells (Kim et al, 2014; Kuang et al, 2017), further upstream causes are not completely known
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