Abstract LB-61: Inhibiting “Dedifferentiation” in breast cancer cells using Honokiol - a plant derived polyphenol

Abstract

Introduction: Dedifferentiation involves terminally differentiated cells reverting back to less differentiated cells such as precursor cells or stem cells within their own lineage allowing the cells to proliferate again before re-differentiation. Tumorigenesis involves uncontrolled cell proliferation and many host-related factors aid in dedifferentiation of tumor cells into stem cell like phenotypes hence providing a mechanism leading to tumor heterogeneity and aggressiveness. Pluripotency factors Oct4, Nanog and Sox2 have been implicated in dedifferentiation and are highly expressed in tumors. The importance of active constitutive agents in natural products has become increasingly apparent owing to their potential cancer chemopreventive and therapeutic properties. Honokiol (HNK) is a natural phenolic compound isolated from an extract of seed cones from Magnolia grandiflora. Recent studies from our laboratory demonstrated that HNK has suppressing effects on different aspects of cancer progression. The present study was designed to specifically examine the potential of HNK to inhibit pluripotency related transcription factors and reverse the process of dedifferentiation associated with uncontrolled cell proliferation in tumorigenesis. Results: Here, we provide evidence that HNK inhibits the ability of breast cancer cells to form mammospheres. HNK treatment inhibits dedifferentiation/pluripotency markers Oct4, Nanog, Sox2 in MCF-7, MDA-MB-231, T47D, MDA-MB-468 breast cancer cells. An analysis of underlying signaling mechanism reveal that HNK inhibits phosphorylation of Stat3 and the downregulation of pluripotency factors is mediated via inhibition of Stat3. Stat3 inhibitor, Stattic potentiates the effect of HNK while overexpression of constitutively active Stat3 interferes with HNK-mediated inhibition of Oct4, Nanog and Sox2. It is interesting to note that HNK treatment also increases the expression of upstream kinase and tumor suppressor LKB1. Utilizing LKB1-null cells and gain-of-function strategies, we show that HNK-mediated inhibition of Oct4, Nanog and Sox2 is regulated by tumor suppressor LKB1. The ability of HNK to inhibit mammosphere formation is abrograted in breast cancer cells stably-silenced for LKB1. In vitro and in vivo analyses show novel functional interactions between HNK, Stat3, LKB1 and dedifferentiation/pluripotency markers. Conclusions: Taken together, these studies provide evidence for a previously unrecognized cross-talk between HNK and dedifferentiation/pluripotency markers Oct4, Nanog, Sox2 via tumor suppressor LKB1-Stat3 axis in inhibiting “dedifferentiation” in breast cancer. Citation Format: Sonali Sengupta, Michael Y. Bonner, Jack L. Arbiser, Neeraj K. Saxena, Dipali Sharma. Inhibiting “Dedifferentiation” in breast cancer cells using Honokiol - a plant derived polyphenol. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-61. doi:10.1158/1538-7445.AM2014-LB-61