Human DNAJA1 Protein: A Potential Novel Therapeutic Target for Pancreatic Cancer

Pancreatic cancer carries the lowest survival rate of all major organ cancers and is the third leading contributor to cancer mortality in the western world. Treatment options for pancreatic ductal adenocarcinoma (PDAC) advanced stage largely remain ineffective despite decades of improvement efforts. Besides surgical intervention, existing chemotherapy treatments are ineffective as a result of chemotherapeutic resistance reported in most pancreatic ductal adenocarcinoma patients. Therefore, an urgent need arises to come up with alternative interventions in PDAC management.

Metabolic dysregulation has presented a promising nonchemotherapeutic PDAC treatment option. Metabolomics is rapidly emerging as an important tool in understanding disease mechanisms and identifying novel therapeutic strategies and it is now an invaluable tool in  drug discovery. Pancreatic ductal adenocarcinoma metabolomic analyses could improve in vivo drug efficacy, drug action, and drug metabolism. Unfortunately, metabolic dysregulation in pancreatic ductal adenocarcinoma could result in drug resistance and contribute to other conditions specific to the carcinogenic state at the same time.

Heat shock proteins are families of proteins synthesized by cells as a consequence of stresses. These proteins are known as molecular chaperones with multiple cellular protective functions. Their chaperone activity is indispensable in a variety of cellular functions. Heat shock protein 40 family, which is often cited as cochaperones of heat shock protein 70, is increasingly becoming valuable in cancer research due to its potential as a therapeutic target.

Heat shock protein 40 family members often accompany other proteins that are either oncogenic or tumor-suppressing. Profiling normal and cancerous pancreatic tissues has reported more than four times downregulation in the expression of heat shock protein 40 member DNAJA1. This protein family member is thought to be implicated in cancer progression, impacts p53 localizations, increases tumorigenicity, and mediates macro-autophagy.

The cellular functions of the familial subclass A of Hsp40s have increased interest in DNAJA1’s role in pancreatic ductal adenocarcinoma and its therapeutic target value. In light of these, researchers Heidi E. Roth, Dr. Fatema Bhinderwala, Dr. Rodrigo Franco, Dr. You Zhou, and led by Professor Robert Powers from The University of Nebraska-Lincoln, induced an increased DNAJA1 expression in pancreatic ductal adenocarcinoma cells in a bid to look into its role in cellular functions. Their study investigated the cellular response as a result of DNAJA1 overexpression in PDAC cell lines, and its overall effect in pancreatic cancer metabolism. Their research work is published in the Journal of Proteome Research.

The authors investigated the metabolic effects of increased DNAJA1 expression implementing a blend of untargeted metabolomics, confocal microscopy, stable isotope-resolved metabolomics, cell-based assays, and flow cytometry. Their investigation uncovered the oncogenic role of DNAJA1 in PDAC.

DNAJA1 overexpression led to increased Warburg effect. This was responsible for overconsumption of glucose to produce metabolites, which augment cellular proliferation. Through the proposed stable isotope-resolved metabolomics approach, the authors observed a decline in ¹³C₆-glucose and an increase in synthesis of pyruvate, alanine, lactate, fructose-6-phosphate, and PEP. The authors also reported an increase in energy metabolites which maintained glycolysis.

DNAJA1 also affected TCA cycle intermediates, which enhanced mitochondrial network fusion, anti-apoptosis, and augmented redox tolerance. Put together, these metabolic changes reinforce DNAJA1’s proto-oncogenic role in pancreatic ductal adenocarcinoma but are however inconsistent with a basic metabolic protein overexpression signature.

DNAJA1 overexpression also resulted in mitochondrial fusion, increased Bcl-2 expression, moderate protection from redox-induced cell death, and elevated cell invasiveness in BxPC-3. The reported differences were however higher in BxPC-3, which contains a loss-of-function mutation in SMAD4, a tumor-suppressing gene.

The study findings indicate a proto-oncogenic function of DNAJA1 in pancreatic ductal adenocarcinoma progression and propose that DNAJA1 could also synergistically work with other proteins with disrupted roles in pancreatic cancer cell lines. In a statement to Medicine Innovates series, Professor Robert Powers said “What is potentially very exciting about cochaperones like DNAJA1 is that they may function by stabilizing mutant proteins that are critical drivers of pancreatic cancer or cancers in general. In this manner, disrupting these DNAJA1-protein complexes may present a completely novel means of treating cancers”.