Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer

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.

Targeting the Calcium Signalling Machinery in Cancer

“…PMCA has been shown to have an important role in cancer [ 157 , 158 , 231 ]. Overexpression of PMCA4 in PDAC correlates with poor prognosis, while siRNA knockdown of PMCA4 inhibited migration and apoptosis resistance in cultured PDAC cells [ 232 ]. In the breast, PMCA has an important role in the normal physiology and in tumorigenesis.…”

“…This is particularly relevant because almost every Ca 2+ channel/transporter is exquisitely sensitive to pH, especially CRAC channels [ 268 , 269 ], and the acid-sensing Ca 2+ -permeable ion channels (ASICs) have important roles in both cancer cells [ 270 , 271 , 272 , 273 ] and immune cells [ 274 , 275 , 276 ]. Moreover, the acidic tumour microenvironment would be expected to impact Ca 2+ -signalling in both cancer cells [ 232 ] and immune cells [ 277 , 278 ] by promoting PMCA activity. This is because ATP-driven PMCAs are Ca 2+ /H + exchangers, and thus their Ca 2+ efflux activity is facilitated by extracellular acidification and inhibited by extracellular alkalinisation [ 279 , 280 ].…”

High-content single-cell combinatorial indexing

“…Differences between the aggregated contact maps between clusters were then used to assess unique translocation and inversion events across the sampled cells. We found that our single-cell contact data uncovers an intrachromosomal translocation between the 8.5-9.5 Mbp and 88.5-91.0 Mbp regions of chromosome 12 (Figure 2k), containing ATP2B1, which is commonly overexpressed in PDAC 30 and the tumor suppressor gene DUSP6 31 that is only present in PDAC-1.…”

Ca2+ Signaling and Its Potential Targeting in Pancreatic Ductal Carcinoma

“…However, the alternate splicing of this gene mRNA transcripts results in a diverse array of more than 30 splice variants. These isoforms are expressed in different areas of the body: PMCA2–3 are “rapid response pumps” expressed in excitatory cells like muscle cells; PMCA1–4 are ubiquitous throughout all tissues in humans, while PMCA4 seems to have a specific role in proliferative signaling, NF-κB nuclear translocation, tumor necrosis factor (TNF)-induced cell death and migration, which all are important pathways for the cancer hallmarks conservation [ 17 ].…”