Abstract
Patients with pancreatic ductal adenocarcinoma (PC) have a poor prognosis due to metastases and chemoresistance. PC is characterized by extensive fibrosis, which creates a hypoxic microenvironment, and leads to increased chemoresistance and intracellular oxidative stress. Thus, proteins that protect against oxidative stress are potential therapeutic targets for PC. A key protein that maintains genomic integrity against oxidative damage is MutY-Homolog (MYH). No prior studies have investigated the function of MYH in PC cells. Using siRNA, we showed that knockdown of MYH in PC cells 1) reduced PC cell proliferation and increased apoptosis; 2) further decreased PC cell growth in the presence of oxidative stress and chemotherapy agents (gemcitabine, paclitaxel and vincristine); 3) reduced PC cell metastatic potential; and 4) decreased PC tumor growth in a subcutaneous mouse model in vivo. The results from this study suggest MYH may be a novel therapeutic target for PC that could potentially improve patient outcome by reducing PC cell survival, increasing the efficacy of existing drugs and reducing metastatic spread.
Highlights
Pancreatic ductal adenocarcinoma [ referred to as pancreatic cancer (PC)] is a highly metastatic and chemoresistant disease with a dismal 5-year survival rate at 7% [1, 2]
We investigated MYH expression in protein extracts from normal human pancreatic ductal epithelial cells (HPDE cells) and the PC cell lines MiaPaCa-2, HPAFII, Panc-1 and AsPC-1 (MiaPaCa-2, Panc-1: primary tumor-derived; HPAFII and AsPC-1: metastases-derived)
Abundant MYH protein was detected in all lines including Human Pancreatic Ductal Epithelial (HPDE) cells, though levels were variable between PC cells (Figure 1C)
Summary
Pancreatic ductal adenocarcinoma [ referred to as pancreatic cancer (PC)] is a highly metastatic and chemoresistant disease with a dismal 5-year survival rate at 7% [1, 2]. Hypoxia and nutrient-deprivation drive the Warburg effect (a switch from oxidative to glycolytic energy production) and the transition of cancer cells from an epithelial phenotype, to a more metastatic and chemoresistant mesenchymal phenotype [8,9,10,11]. These features impose additional oxidative stress on PC cells. This is because hypoxia induces the release of reactive oxygen species (ROS) from mitochondria, initiating a signaling cascade to facilitate cell survival [12]. The Warburg effect results in loss of potent anti-oxidant intermediates, reducing the ability of cancer cells to mop-up ROS [9]
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