Variation in human cancer cell external phosphatidylserine is regulated by flippase activity and intracellular calcium

// Subrahmanya D. Vallabhapurapu 1 , Víctor M. Blanco 1 , Mahaboob K. Sulaiman 1 , Swarajya Lakshmi Vallabhapurapu 1 , Zhengtao Chu 1,2 , Robert S. Franco 1 and Xiaoyang Qi 1,2 1 Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA 2 Divison of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA Correspondence to: Xiaoyang Qi, email: // Keywords : phosphatidylserine, surface exposure, cancer cell biomarker, flippase, calcium Received : August 27, 2015 Accepted : September 09, 2015 Published : October 09, 2015 Abstract Viable cancer cells expose elevated levels of phosphatidylserine (PS) on the exoplasmic face of the plasma membrane. However, the mechanisms leading to elevated PS exposure in viable cancer cells have not been defined. We previously showed that externalized PS may be used to monitor, target and kill tumor cells. In addition, PS on tumor cells is recognized by macrophages and has implications in antitumor immunity. Therefore, it is important to understand the molecular details of PS exposure on cancer cells in order to improve therapeutic targeting. Here we explored the mechanisms regulating the surface PS exposure in human cancer cells and found that differential flippase activity and intracellular calcium are the major regulators of surface PS exposure in viable human cancer cells. In general, cancer cell lines with high surface PS exhibited low flippase activity and high intracellular calcium, whereas cancer cells with low surface PS exhibited high flippase activity and low intracellular calcium. High surface PS cancer cells also had higher total cellular PS than low surface PS cells. Together, our results indicate that the amount of external PS in cancer cells is regulated by calcium dependent flippase activity and may also be influenced by total cellular PS.