Abstract B02: Honokiol attenuates stemness, growth and metastasis of pancreatic tumor cells: A novel natural agent for therapy and prevention

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in the United States with a five year survival rate at just 6.0%. Its poor clinical outcome is largely attributed to its aggressive and metastatic nature as well as refractoriness to currently available therapeutic modalities. Hence, there is a critical need to develop novel and more effective treatments for this malignancy. We previously reported that honokiol (HNK), a phytochemical isolated from the leaves and bark of Magnolia grandiflora, suppresses the growth of PC cells. Moreover, HNK sensitized PC cells to gemcitabine by preventing its activation of NF-kB pathway. Here, we have further analyzed the effects of HNK on clonogenicity, stemness, tumorigenicity and metastasis by performing in vitro and in vivo functional assays. Furthermore, we have conducted biochemical, histological and immunohistochemical analyses on vehicle and HNK-treated tumor cells and xenografts to examine the mechanism of action and molecular targets of HNK. We report that HNK treatment reduces the clonogenicity and stemness of PC cells as well as limits their capability to migrate and invade through the extracellular matrix. Our animal studies demonstrate that HNK significantly impedes the growth of pancreatic tumors and reduces the incidence as well as extent of metastases. Histological and immunohistochemical analyses suggest a decrease in desmoplasia, which is a key feature of pancreatic adenocarcinomas, acting as a physical barrier for drug delivery. At the molecular level, we have observed that HNK decreases the expression of hedgehog pathway through suppression of SHH production in PC cells. Further, we demonstrate a suppression of CXCR4 (a receptor for stromal cell derived chemokine, CXCL12) after treatment with HNK in a dose- and time-dependent manner. This is highly significant considering the known functions of SHH/CXCR4 signaling axes in growth, invasion, metastasis and therapeutic resistance of pancreatic tumor cells. Using transient transfection of constitutively active IKKB; mutant (pCMV-IKKB; S177E S181E) to neutralize the suppressive effect of HNK on NF-kB activation, we reveal its partial role in downregulation of CXCR4 and SHH expression. Together, our findings suggest that HNK likely impacts multiple molecular pathways to confer its anti-tumor activity and thus support its potential utility as a novel agent for PC therapy and/or prevention. Citation Format: Courey A. Averett, Arun Bhardwaj, Sumit Arora, Sanjeev Srivastava, Seema Singh, JE Carter, Ajay P. Singh. Honokiol attenuates stemness, growth and metastasis of pancreatic tumor cells: A novel natural agent for therapy and prevention. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr B02.