Abstract
The study of the cancer secretome is gaining even more importance in cancers such as pancreatic ductal adenocarcinoma (PDAC), whose lack of recognizable symptoms and early detection assays make this type of cancer highly lethal. The wild-type p53 protein, frequently mutated in PDAC, prevents tumorigenesis by regulating a plethora of signaling pathways. The importance of the p53 tumor suppressive activity is not only primarily involved within cells to limit tumor cell proliferation but also in the extracellular space. Thus, loss of p53 has a profound impact on the secretome composition of cancer cells and marks the transition to invasiveness. Here, we demonstrate the tumor suppressive role of wild-type p53 on cancer cell secretome, showing the anti-proliferative, apoptotic and chemosensitivity effects of wild-type p53 driven conditioned medium. By using high-resolution SWATH-MS technology, we characterized the secretomes of p53-deficient and p53-expressing PDAC cells. We found a great number of secreted proteins that have known roles in cancer-related processes, 30 of which showed enhanced and 17 reduced secretion in response to p53 silencing. These results are important to advance our understanding on the link between wt-p53 and cancer microenvironment. In conclusion, this approach may detect a secreted signature specifically driven by wild-type p53 in PDAC.
Highlights
Licensee MDPI, Basel, Switzerland.Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid tumors and its incidence is increasing worldwide [1,2]
We aimed to study whether wild-type p53 (WTp53) may exhibit suppressor roles through its influence on the secretome of pancreatic ductal adenocarcinoma (PDAC) cells, in accordance with the tumor suppressor role of WTp53
The importance of p53 target gene spectrum is reflected in the tumor microenvironment through the regulation of numerous genes encoding for secreted proteins that trigger changes outside of the tumor cell [34,35]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most invasive solid tumors and its incidence is increasing worldwide [1,2]. The molecular complexity and the absence of early specific symptoms, as well as the efficient methods for its early detection, ensure that only about 20% of pancreatic cancers are detected early enough to be surgically resectable [3]. Around 50% of diagnosed PDAC patients present with metastatic disease [3]. One of the most important proteins involved in inducing cell cycle arrest, DNA.
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