Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53-NF kappa B crosstalk

摘要

Poor pancreatic cancer (PC) prognosis 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-signalling pathways. p53 is mutated in more than 50% of PC and NF kappa B is constitutively activated in therapy-resistant residual disease; these mutations and activations account for the avoidance of cell death and metastasis. Recently, we demonstrated the anti-PC potential of fucoidan extract from marine brown alga, Turbinaria conoides (J. Agardh) Kutzing (Sargassaceae). In this study, we aimed to characterize the active fractions of fucoidan extract to identify their select anti-PC efficacy, and to define the mechanism(s) involved. Five fractions of fucoidan isolated by ion exchange chromatography were tested for their potential in genetically diverse human PC cell lines. All fractions exerted significant dose-dependent and time-dependent regulation of cell survival. Fucoidans induced apoptosis, activated caspase -3, -8 and -9, and cleaved Poly ADP ribose polymerase (PARP). Pathway-specific transcriptional analysis recognized inhibition of 57 and 38 nuclear factor kappa B (NF kappa B) pathway molecules with fucoidan-F5 in MiaPaCa-2 and Panc-1 cells, respectively. In addition, fucoidan-F5 inhibited both the constitutive and Tumor necrosis factor-alpha (TNF alpha)-mediated NF kappa B DNA-binding activity in PC cells. Upregulation of cytoplasmic I B levels and significant reduction of NF kappa B-dependent luciferase activity further substantiate the inhibitory potential of seaweed fucoidans on NF kappa B. Moreover, fucoidan(s) treatment increased cellular p53 in PC cells and reverted NF kappa B forced-expression-related p53 reduction. The results suggest that fucoidan regulates PC progression and that fucoidans may target p53-NF kappa B crosstalk and dictate apoptosis in PC cells.