DNAJA1 Dysregulates Metabolism Promoting an Antiapoptotic Phenotype in Pancreatic Ductal Adenocarcinoma

The cochaperone protein DNAJA1 (HSP40) is downregulated four-fold in pancreatic cancer cells. The impact of DNAJA1 expression on pancreatic ductal adenocarcinoma (PDAC) progression remains unclear. The metabolic impacts of increased DNAJA1 expression were evaluated using a combination of untargeted metabolomics, stable isotope-resolved metabolomics (SIRM), confocal microscopy, flow cytometry, and cell-based assays. Differential Warburg glycolysis, an increase in redox currency, and alterations in amino acid levels were observed in both overexpression cell lines. DNAJA1 overexpression also led to mitochondrial fusion, an increase in the expression of Bcl-2, a modest protection from redox-induced cell death, a loss of structural integrity due to the loss of actin fibers, and an increase in cell invasiveness in BxPC-3. These differences were more pronounced in BxPC-3, which contains a loss-of-function mutation in the tumor-suppressing gene SMAD4. These findings suggest a proto-oncogenic role of DNAJA1 in PDAC progression and suggest DNAJA1 may function synergistically with other proteins with altered activities in pancreatic cancer cell lines.