Abstract
Simple SummaryResistance to oxaliplatin remains a major challenge in pancreatic cancer therapy. However, molecular mechanisms underlying oxaliplatin resistance in pancreatic cancer is still unclear. The aim of this study was to identify global changes of proteins involved in oxaliplatin resistance in pancreatic cancer cells, thereby elucidating the multiple mechanisms of oxaliplatin resistance in pancreatic cancer. We presented the quantitative proteomic profiling of oxaliplatin-resistant pancreatic cancer cells via a stable isotope labelling by amino acids in cell culture (SILAC)-based shotgun proteomic approach. Multiple biological processes including DNA repair, cell cycle process, and type I interferon signaling pathway were enriched in oxaliplatin-resistant pancreatic cancer cells. Furthermore, we demonstrated that both Wntless homolog protein (WLS) and myristoylated alanine-rich C-kinase substrate (MARCKS) could participate in oxaliplatin resistance in pancreatic cancer cells.Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of pancreatic cancer. Understanding the cellular mechanisms of oxaliplatin resistance is important for developing new strategies to overcome drug resistance in pancreatic cancer. In this study, we performed a stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics analysis of oxaliplatin-resistant and sensitive pancreatic cancer PANC-1 cells. We identified 107 proteins whose expression levels changed (thresholds of 2-fold changes and p-value ≤ 0.05) between oxaliplatin-resistant and sensitive cells, which were involved in multiple biological processes, including DNA repair, cell cycle process, and type I interferon signaling pathway. Notably, myristoylated alanine-rich C-kinase substrate (MARCKS) and Wntless homolog protein (WLS) were upregulated in oxaliplatin-resistant cells compared to sensitive cells, as confirmed by qRT-PCR and Western blot analysis. We further demonstrated the activation of AKT and β-catenin signaling (downstream targets of MARCKS and WLS, respectively) in oxaliplatin-resistant PANC-1 cells. Additionally, we show that the siRNA-mediated suppression of both MARCKS and WLS enhanced oxaliplatin sensitivity in oxaliplatin-resistant PANC-1 cells. Taken together, our results provide insights into multiple mechanisms of oxaliplatin resistance in pancreatic cancer cells and reveal that MARCKS and WLS might be involved in the oxaliplatin resistance.
Highlights
Pancreatic cancer is one of the most lethal cancers, with the five-year survival rate of 8%, the lowest survival rate among other common types of cancer [1]
The use of oxaliplatin is effective in the treatment of cancers, acquired resistance to oxaliplatin often occurs in patients, which leads to therapeutic failures
The aim of this study is to investigate the global proteomic changes associated with acquired oxaliplatin resistance in pancreatic cancer cells
Summary
Pancreatic cancer is one of the most lethal cancers, with the five-year survival rate of 8%, the lowest survival rate among other common types of cancer [1]. Despite recent advances in cancer therapeutics, pancreatic cancer still has a poor prognosis because it has no distinctive symptoms in early stages, and often spread to other organs before it is diagnosed. Both intrinsic and acquired chemoresistance are a main cause of failure in chemotherapy treatment of pancreatic cancer [2,3,4]. Oxaliplatin is a platinum-based chemotherapy drug used in the treatment of various types of cancers, including pancreatic, colorectal, and gastric cancers [5,6,7]. Understanding of multiple mechanisms for acquired oxaliplatin resistance remains a challenge in pancreatic cancer treatments
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