Opioids increase bladder cancer cell migration via bradykinin B2 receptors

Abstract

Abstract. Data relating opioid treatment and modification of cancer cell migration (a prerequisite of metastasis) both in vitro and in vivo are diverging. In the present report we show that opioids increase the migratory activity of bladder cancer cells (T24 and EJ) and we provide a new mechanistic insight, explaining (at least partially) their action: we report that the enhanced opioid-related cell migration is controlled (in the absence of opioid receptors) through their interaction with bradykinin B2 receptors. Indeed, in these cell lines, opioids increase migration, adhesion, spreading and invasion by re-arranging actin cytoskeleton, increasing MMP-2 and -9 secretion and triggering specific intracellular signaling cascades in a non-opioid receptor mediated manner. An interaction, albeit with low affinity, of opioids with the bradykinin B2 receptor is reported, resulting in the increase of migration, while B2 antagonists revert this action. A systematic assay of different human epithelial cancer cell lines confirmed that only the B2-positive/opioid receptornegative bladder cancer cells present this opioid-related increased migration/invasive phenotype. We suggest that opioid administration in cancer patients should be re-evaluated, keeping in mind that they may have other beneficial (protection) or adverse effects (spreading of cancer cells), in spite of their unique role in pain relief. IntroductionA number of studies report that opioids (secreted endogenously or exogenously administered) are implicated in tumor growth, progression and metastasis (1,2). Extensive work has been performed in the field of cancer cell proliferation and apoptosis; however, scarce, heterogeneous, or conflicting data occur, on opioid effect in cell motility and metastasis. Morphine was found to decrease tumor metastasis (3,4), either through a direct action on colon cancer tumor cells (5,6), or by attenuating stress (3,4). Other opioids were found to increase cell motility and invasion of breast and small cell lung carcinoma (7,8), or to have no effect (pancreatic, colon, and head and neck carcimona) (9). Conversely, very few indirect data concern opioid effects in the genitourinary system: Patel et al reported that opiate addiction results in progression of urogenital injury (10), while opioid agonists were shown to decrease cell proliferation of opossum kidney (OK) cells (11).The majority of deaths in bladder cancer are due to tumor ability to invade the bladder wall and demonstrate a high propensity for lymphatic and distant metastases. In the present study we have investigated the direct action of opioids (with different receptor selectivity), on the metastatic potential (migratory activity, adhesion, spreading and invasion) of T24 and EJ bladder cancer cells. Our results indicate that opioids can increase the migration of bladder cancer cells, by triggering specific signaling cascades. Their action is not mediated by opioid receptors, but involves bradykinin B2 receptor activation, providing new insights into the role of opioi...

Involvement of Intercellular Adhesion Molecule-1 Up-Regulation in Bradykinin Promotes Cell Motility in Human Prostate Cancers

“…Several recent studies indicated that BK can promote proliferation, invasion, and migration in different cell types via BK receptors, suggesting that BK receptors play critical roles in tumor metastasis [18–20]. Interestingly, the B2 receptor, rather than the B1 receptor, is commonly involved in most biological actions that are BK-mediated [20,21]. …”