Abstract
Abstract Poor prognosis of pancreatic cancer (PC) has been attributed to its resistance to apoptosis and propensity for early systemic dissemination. Existing therapeutic strategies are often circumvented by the molecular crosstalk between cell signaling pathways. The fact that p53 is mutated in more than 50% of PC tissues and NFκB is constitutively activated in therapy resistant residual PC accounts for the evaded cell death and dissemination. In this study, we examined the benefit of fucoidan from a marine brown alga, Turbinaria conoides against PC progression. Five fractions of fucoidan isolated and fractionated using ion exchange chromatography were tested for their potential in this setting using two (MiaPaCa-2, Panc-1) genetically diverse human PC cell-lines. All fractions investigated exerted significant dose dependent and time dependent regulation of cell survival. Coherently, fucoidans induced apoptosis and activated caspase -3, -8 and -9 and cleaved PARP. Pathway-specific transcriptional analysis (QPCR profiling) recognized inhibition of 57 and 38 NFκB pathway molecules with fucoidan-F5 in MiaPaCa-2 and Panc-1 cells, respectively. In addition, fucoidan-F5 was also found to inhibit both the constitutive and TNFα mediated NFκB DNA-binding activity (EMSA) in PC cells. Upregulation of cytoplasmic IκB levels and significant reduction of NFκB dependent luciferase activity further substantiate inhibitory potential of seaweed fucoidans on NF-κB. Moreover, fucoidan(s) treatment increases cellular p53 in PC cells. Together, the results suggests that fucoidan regulates PC progression and further imply that fucoidans may selectively target p53-NFκB crosstalk and dictate apoptosis in PC cells. Citation Format: Caroline R. Delma, Guru Prasad Srinivasan, Nune Raviprakash, Sunil K. Manna, Somasundaram T. Somasundaram, Natarajan Aravindan. Fucoidan from Turbinaria conoides attenuates pancreatic cancer progession by regulating p53 - NFκB crosstalk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5508. doi:10.1158/1538-7445.AM2015-5508
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