Abstract
BackgroundCurcumin inhibits the growth of pancreatic cancer tumor xenografts in nude mice; however, the mechanism of action is not well understood. It is becoming increasingly clear that RNA binding proteins regulate posttranscriptional gene expression and play a critical role in RNA stability and translation. Here, we have determined that curcumin modulates the expression of RNA binding protein CUGBP2 to inhibit pancreatic cancer growth.Methodology/Principal FindingsIn this study, we show that curcumin treated tumor xenografts have a significant reduction in tumor volume and angiogenesis. Curcumin inhibited the proliferation, while inducing G2-M arrest and apoptosis resulting in mitotic catastrophe of various pancreatic cancer cells. This was further confirmed by increased phosphorylation of checkpoint kinase 2 (Chk2) protein coupled with higher levels of nuclear cyclin B1 and Cdc-2. Curcumin increased the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) mRNA, but protein levels were lower. Furthermore, curcumin increased the expression of RNA binding proteins CUGBP2/CELF2 and TIA-1. CUGBP2 binding to COX-2 and VEGF mRNA was also enhanced, thereby increasing mRNA stability, the half-life changing from 30 min to 8 h. On the other hand, silencer-mediated knockdown of CUGBP2 partially restored the expression of COX-2 and VEGF even with curcumin treatment. COX-2 and VEGF mRNA levels were reduced to control levels, while proteins levels were higher.Conclusion/SignificanceCurcumin inhibits pancreatic tumor growth through mitotic catastrophe by increasing the expression of RNA binding protein CUGBP2, thereby inhibiting the translation of COX-2 and VEGF mRNA. These data suggest that translation inhibition is a novel mechanism of action for curcumin during the therapeutic intervention of pancreatic cancers.
Highlights
Despite the advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem in the United States [1]
To begin evaluating the role of curcumin on tumor proliferation in vivo, we examined the ability of curcumin to suppress the growth of mouse pancreatic cancer cell xenografts in nude mice
Curcumin significantly inhibited the growth of the tumor xenografts (Fig. 1A)
Summary
Despite the advances in molecular pathogenesis, pancreatic cancer remains a major unsolved health problem in the United States [1]. Pancreatic cancer is a rapidly invasive, metastatic tumor, which is resistant to standard therapies [2,3]. Single agent based chemotherapy (e.g. Gemcitabine) is the mainstay treatment for metastatic adenocarcinoma of pancreas. Gemcitabine treatment has a tumor response rate of below 10%; none of the available current chemotherapeutic agents have an objective response rate of over 10% [4,5]. Curcumin inhibits the growth of pancreatic cancer tumor xenografts in nude mice; the mechanism of action is not well understood. It is becoming increasingly clear that RNA binding proteins regulate posttranscriptional gene expression and play a critical role in RNA stability and translation. We have determined that curcumin modulates the expression of RNA binding protein CUGBP2 to inhibit pancreatic cancer growth
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