No abstract

Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-kB, and suppressed the NF-kB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-kB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-kB-and NF-kB-regulated gene products.Cancer Prev Res; 9(3); 234-44. Ó2015 AACR.

Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1‐AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1‐AS1 for PDAC patients was explored, and the effects of TPT1‐AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1‐AS1 was highly expressed in PDAC, and high TPT1‐AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1‐AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial‐to‐mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1‐AS1 functioned as an endogenous sponge for miR‐30a‐5p, which increased integrin β3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1‐AS1 promoter and affected the expression of TPT1‐AS1, thus forming a positive feedback loop with TPT1‐AS1. Taken together, our results uncovered a reciprocal loop of TPT1‐AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1‐AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients.