Downregulation of Mucin1 in Cancer Cells is Associated with Modulation of Calcium Signalling Pathways and Alteration in Procoagulant Related Activity

Abstract

Background Intracellular calcium ions play an essential role in regulating numerous physiological functions by acting as a second messenger in signal transduction pathways. Alterations in calcium signaling are also implicated in several pathological conditions including cancer. Aim The purpose of this study is to investigate whether MUC1, a well-established tumor marker, plays a role in modulating calcium signalling in cancer cells. Methods MUC1 knockdown breast cancer MCF-7 cells were used to investigate whether the overexpression of MUC1 by cancer cells has an influence on calcium signalling pathways, by determining the level of a range of calcium signalling proteins and the dynamics of intracellular calcium mobilization as well as the cellular effects induced by calcium treatment. The investigation was also extended to normal human mammary epithelial, human breast and pancreatic cancer cell lines, which express different levels of MUC1. Result MUC1 downregulation altered the aberrant expression of several calcium transporter proteins in MCF-7 cancer cells. The level of each of these calcium signaling pathways proteins was correlated to MUC1 level in normal human mammary epithelial, human breast and pancreatic cancer cell lines. Consequently, a number of proteins whose activities are calcium dependent such as p-CaMKII, and pro-coagulant proteins Va, Xa and thrombin were found to be reduced in MUC1 downregulated MCF-7 cells. In addition, the effect of thrombin on calcium mobilization and the cleavage of the thrombin receptors was also reduced in MUC1 downregulated MCF-7 cells. Conclusion The downregulation of MUC1 is capable of modulating calcium cellular effects via alteration in the expression of calcium signalling proteins and by impacting calcium induced initiation of procoagulant activity, which is capable of influencing the effect of thrombin on cancer cells. Such properties contribute to another crucial role for MUC1 within the signalling network associated with tumorigenesis.