Calcium Channel α2δ1 is Essential for Pancreatic Tumor-Initiating Cells through Sequential Phosphorylation of PKM2

BACKGROUND & AIMS: Tumor-initiating cells (TICs) drive pancreatic cancer tumorigenesis, therapeutic resistance, and metastasis. However, TICs are highly plastic and heterogenous, which impede the robust identification and targeted therapy of such a population. The aim of this study is to identify the surface marker and therapeutic target for pancreatic TICs. METHODS: We isolated voltage-gated calcium channel alpha 2 delta 1 subunit (isoform 5)-positive subpopulation from pancreatic cancer cell lines and freshly resected primary tissues by fluorescence-activated cell sorting and evaluated their TIC properties by spheroid formation and tumorigenic assays. Coimmunoprecipitation was used to identify the direct substrate of CaMKIId. RESULTS: We demonstrate that the voltage-gated calcium channel alpha 2 delta 1 subunit (isoform 5) marks a subpopulation of pancreatic TICs with the highest TIC frequency among the known pancreatic TIC markers tested. Furthermore, alpha 2 delta 1 is functionally sufficient and indispensable to promote TIC properties by mediating Ca2+ influx, which activates CaMKIId to directly phosphorylate PKM2 at T454 that results in subsequent phosphorylation at Y105 to translocate into nucleus, enhancing the stem-like properties. Interestingly, blocking alpha 2 delta 1 with its specific antibody has remarkably therapeutic effects on pancreatic cancer xenografts by reducing TICs. CONCLUSIONS: alpha 2 delta 1 promotes pancreatic TIC properties through sequential phosphorylation of PKM2 mediated by CaMKIId, and targeting alpha 2 delta 1 provides a therapeutic strategy against TICs for pancreatic cancer.