Abstract
Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca2+ ([Ca2+]i) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC.
Highlights
Pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is a commonly diagnosed cancer with the lowest 5-year survival rate of all cancers [1]
The current study identified plasma membrane calcium ATPase-4 (PMCA4) as a potential candidate as it appears to be almost uniquely over-expressed in MIA PaCa-2 cells similar to human PDAC tumors, making these an ideal model cell line to study the role of PMCA4 in PDAC
Over-expression of PMCA4 is observed in patient PDAC tumors and is correlated with poor patient survival
Summary
Pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is a commonly diagnosed cancer with the lowest 5-year survival rate of all cancers [1]. The early stages of pancreatic cancer are often asymptomatic resulting in advanced stage diagnosis, with high metastatic tumor burden [2]. Conventional chemotherapeutics, involving combinations of gemcitabine/nab-paclitaxel, have minimally improved the survival of pancreatic cancer patients over the past three decades [3]. Dysregulation of calcium (Ca2+ ) signaling has been reported to facilitate malignancies in multiple types of cancer, including PDAC [4]. Spatiotemporal shaping of Ca2+ signaling is critical for regulating numerous physiological processes in all cells [5]. This can only be achieved if cytosolic
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