The following is the summary of “Calcium Channel α2δ1 is Essential for Pancreatic Tumor-Initiating Cells through Sequential Phosphorylation of PKM2” published in the January 2023 issue of Cellular and Molecular Gastroenterology and Hepatology by Liu, et al.

For pancreatic cancer, carcinogenesis, treatment resistance, and metastasis for pancreatic cancer are all driven by tumor-initiating cells (TICs). However, the plasticity and heterogeneity of TICs make it difficult to identify and treat this population reliably. Finding a treatment target and surface marker for pancreatic TICs is the focus of this research. To assess the TIC features of pancreatic cancer cell lines and newly resected primary tissues, we used fluorescence-activated cell sorting to select a subpopulation positive for the voltage-gated calcium channel α2δ1 subunit (isoform 5). CaMKII’s direct substrate was determined by coimmunoprecipitation.

Researchers show that among the known pancreatic TIC indicators evaluated, the 21 subunit (isoform 5) of the voltage-gated calcium channel is the best identifier of a TIC-rich subpopulation. In addition, 21 is both necessary and sufficient for promoting TIC characteristics via facilitating Ca2+ influx, which stimulates CaMKIIδ to directly phosphorylate PKM2 at T454, which in turn causes PKM2 to translocate into the nucleus via phosphorylation at Y105, so boosting the stem-like features. 

To add intrigue, inhibiting 21 with its particular antibody exhibits remarkable therapeutic effects on pancreatic cancer xenografts by decreasing TICs. Tissue inhibitor of kinase α2δ1 (α2δ1) increases pancreatic TIC characteristics by sequentially phosphorylating PKM2 via CaMKII, and targeting 21 offers a treatment option against TICs in pancreatic cancer.