Abstract
The cancer secretome is a rich repository of useful information for both cancer biology and clinical oncology. A better understanding of cancer secretome is particularly relevant for pancreatic ductal adenocarcinoma (PDAC), whose extremely high mortality rate is mainly due to early metastasis, resistance to conventional treatments, lack of recognizable symptoms, and assays for early detection. TP53 gene is a master transcriptional regulator controlling several key cellular pathways and it is mutated in ~75% of PDACs. We report the functional effect of the hot-spot p53 mutant isoforms R175H and R273H on cancer cell secretome, showing their influence on proliferation, chemoresistance, apoptosis, and autophagy, as well as cell migration and epithelial-mesenchymal transition. We compared the secretome of p53-null AsPC-1 PDAC cells after ectopic over-expression of R175H-mutp53 or R273H-mutp53 to identify the differentially secreted proteins by mutant p53. By using high-resolution SWATH-MS technology, we found a great number of differentially secreted proteins by the two p53 mutants, 15 of which are common to both mutants. Most of these secreted proteins are reported to promote cancer progression and epithelial-mesenchymal transition and might constitute a biomarker secreted signature that is driven by the hot-spot p53 mutants in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer; it is characterized by poor prognosis, with a dismal overall five-year survival rate of ~5% [1,2]
We aimed to study the role of mutp53-driven secretome in cancer cell aggressiveness to investigate whether mutant p53 may influence the secretome of PDAC cells
This conditioned medium (CM) released by transfected AsPC-1 cells was transferred to new p53-null AsPC-1 cells, which were cultivated in wtp53- or mutp53-driven secretome for 48 h in order to study the functional effects of secretome driven by GOF R175H and R273H mutp53 isoforms
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer; it is characterized by poor prognosis, with a dismal overall five-year survival rate of ~5% [1,2]. The most frequent p53 alterations are missense mutations in the DNA binding domain (DBD), called hot-spot mutants, which cause the expression of full-length p53 mutant isoforms. These mutations in the DBD are grouped into two main types: conformational mutations, such as mutp53-R175H, and contact mutations, such as mutp53-R273H, which cause structural modifications in the binding domain or affect the DNA binding ability of the protein, respectively [10]. Both kinds of mutations alter p53’s interaction with its consensus DNA-binding sequence, negatively impacting the activation of tumor suppressor wild type-p53 target genes
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