Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of <8%. Therefore, finding new treatment strategies against PDAC cells is an imperative issue. Betulinic acid (BA), a plant-derived natural compound, has shown great potential to combat cancer owing to its versatile physiological functions. In this study, we observed the impacts of BA on the cell viability and migratory ability of PDAC cell lines, and screened differentially expressed proteins (DEPs) by an LC-MS/MS-based proteomics analysis. Our results showed that BA significantly inhibited the viability and migratory ability of PDAC cells under a relatively low dosage without affecting normal pancreatic cells. Moreover, a functional analysis revealed that BA-induced downregulation of protein clusters that participate in mitochondrial complex 1 activity and oxidative phosphorylation, which was related to decreased expressions of RNA polymerase mitochondrial (POLRMT) and translational activator of cytochrome c oxidase (TACO1), suggesting that the influence on mitochondrial function explains the effect of BA on PDAC cell growth and migration. In addition, BA also dramatically increased Apolipoprotein A1 (APOA1) expression and decreased NLR family CARD domain-containing protein 4 (NLRC4) expression, which may be involved in the dampening of PDAC migration. Notably, altered expression patterns of APOA1 and NLRC4 indicated a favorable clinical prognosis of PDAC. Based on these findings, we identified potential proteins and pathways regulated by BA from a proteomics perspective, which provides a therapeutic window for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease and causes the highest mortality rate and the lowest survival rate in the world [1], as well as in Taiwan [2]
Studies have shown that co-administration of the multitarget kinase inhibitor, sorafenib, and betulinic acid (BA) in PDAC cell lines can reduce the proliferation and colony-forming ability of PDAC cell lines without inducing apoptosis [11]; others have found that the chemotherapeutic drug gemcitabine, combined with BA, significantly increased apoptosis of PDAC cell lines compared to an intervention with gemcitabine alone [12], suggesting that BA may synergize antitumor drugs by enhancing the drug’s efficacy and reducing drug resistance
IC50 values of Mia PaCa-2, SUIT-2, and hTERT-HPNE cells were 1.783, 0.505, and 5.689 μM at 24 h, and were 2.908, 0.864, 7.601 μM at 48 h (Table 1, Figure S1). This indicates that BA can impede PDAC cell growth at relatively low concentrations without affecting normal cells, suggesting that BA exhibits selective cytotoxicity
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease and causes the highest mortality rate and the lowest survival rate in the world [1], as well as in Taiwan [2]. Pancreatic ductal adenocarcinoma was the seventh leading cause of cancer-related deaths in Taiwan in 2019, and the number of deaths has been increasing year to year [2]. BA shows selective toxicity towards many different types of tumors without damaging normal cells. The mechanisms of BA against cancer include promoting an endogenous apoptotic response [8], decreasing cancer cell stemness and the epithelial-to-mesenchymal transition (EMT) [9], and inhibiting tumor tissue angiogenesis [10]. Studies have shown that co-administration of the multitarget kinase inhibitor, sorafenib, and BA in PDAC cell lines can reduce the proliferation and colony-forming ability of PDAC cell lines without inducing apoptosis [11]; others have found that the chemotherapeutic drug gemcitabine, combined with BA, significantly increased apoptosis of PDAC cell lines compared to an intervention with gemcitabine alone [12], suggesting that BA may synergize antitumor drugs by enhancing the drug’s efficacy and reducing drug resistance
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