Ai-Xuan Holterman

Multifunctional roles of urokinase plasminogen activator (uPA) in cancer stemness and chemoresistance of pancreatic cancer

This research highlights the multifunctional role of uPA in pancreatic cancer as a regulator of stemness and chemoresistance. uPA is found to be physically associated with the transcription factors Lhx2 and HOXA5 in the nucleus and regulated expression of p53.

Surgical treatment of nonalcoholic fatty liver disease in severely obese patients

Obesity is a multi-organ system disease with underlying metabolic abnormalities and chronic systemic inflammation. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of obesity metabolic dysfunction and its associated cardiovascular- and liver-related morbidities and mortality. Our current understanding of NAFLD pathogenesis, disease characteristics, the role of insulin resistance, chronic inflammation, gut–liver and gut–brain crosstalk and the effectiveness of pharmacotherapy is still evolving. Bariatric surgery significantly improves metabolic and NAFLD histology in severely obese patients, although its positive effects on fibrosis are not universal. Bariatric surgery benefits NAFLD through its metabolic effect on insulin resistance, inflammation, and insulinotropic and anorexinogenic gastrointestinal hormones. Further studies are needed to understand the natural course of NAFLD in severely obese patients and the role of weight loss surgery as a primary treatment for NAFLD.

Abstract 2154: TX1111: a peptide homologue of Topoisomerase-1 sensitizes pancreatic cancer cells to gemcitabine

Pancreatic Ductal Adeno Carcinoma (PDAC) is the fourth most common cause of cancer deaths in the United States and accounts for over 95% of all pancreatic cancers. The combined 1- and 5-year survival rates for PDAC are very poor, at 25% and 6% respectively. A major hallmark of pancreatic cancer is tumor recurrence and extremely poor response to chemotherapy. The current standard of care for patients with advanced pancreatic cancer is a chemotherapy regimen that includes gemcitabine. This treatment results in a modest benefit i.e., an increase in survival of only 5 weeks. The high mortality in patients diagnosed with this pancreatic cancer is primarily due to its drug-resistant nature and the lack of effective therapeutic strategies to overcome drug resistance. This disappointing situation strongly suggests that an improved and increased understanding of drug resistance mechanisms could lead to the development of novel therapeutic strategies for the successful treatment of patients with pancreatic cancer. Our studies have shown that one of the contributing factors that lead to chemotherapy resistance is the protease activator urokinase plasminogen activator (uPA). To validate the contribution of uPA in chemoresistance, we overexpressed uPA in MIAPaCa-2 and PANC-1 cells and determined chemoresistance. We observed that uPA overexpressed cells showed increased chemoresistance in both Mia PaCa-2 (>25 fold) and PANC-1 (>6 fold). Mass-Spec analysis of nuclear uPA-IP from pancreatic cancer cells revealed that uPA interacts with Topoisomerase-1 (TOPO-1). This was further validated by western blot analysis of nuclear co-IP in pancreatic cancer cells. Further the binding domains of TOPO-1 to uPA were identified using overlapping a peptides array (PepSpot-JPT) followed by synthesis of these peptides. We observed that a TOPO-1 homologous peptide designated TX1111 was capable of significantly suppressing gemcitabine resistance in pancreatic cancer cells. Our observations show that the specific peptide TX1111 suppresses chemoresistance by 45% in Mia Paca-2 cells (p These results demonstrate that: 1. Overexpression of uPA promotes gemcitabine resistance in pancreatic cancer cells 2. uPA and TOPO-1 interact in the nucleus of pancreatic cancer cells 3. The peptide homologue of TOPO-1, TX1111 sensitizes gemcitabine resistant pancreatic cancer cells. Citation Format: Manu Gnanamony, Victoria Stepanova, Lily Criscione, Jerusha Boyineni, Stephen J. Marshall, AiXuan Holterman, Christopher S. Gondi. TX1111: a peptide homologue of Topoisomerase-1 sensitizes pancreatic cancer cells to gemcitabine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2154.