Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53 – NFκB crosstalk

Caroline R. Delma, Somasundaram Thirugnanasambandan, Guru Prasad Srinivasan, Nune Raviprakash, Sunil K. Manna, Mohan Natarajan, Natarajan Aravindan

Research output: Contribution to journalArticle

Abstract

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 NFκB 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) Kützing (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 κB (NFκB) 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-α (TNFα)-mediated NFκB DNA-binding activity in PC cells. Upregulation of cytoplasmic IκB levels and significant reduction of NFκB-dependent luciferase activity further substantiate the inhibitory potential of seaweed fucoidans on NFκB. Moreover, fucoidan(s) treatment increased cellular p53 in PC cells and reverted NFκB forced-expression-related p53 reduction. The results suggest that fucoidan regulates PC progression and that fucoidans may target p53–NFκB crosstalk and dictate apoptosis in PC cells.

Original languageEnglish (US)
Article number112078
JournalPhytochemistry
Volume167
DOIs
StatePublished - Nov 1 2019

Fingerprint

fucoidan
Phaeophyta
pancreatic neoplasms
Phaeophyceae
Algae
Crosstalk
Pancreatic Neoplasms
apoptosis
Apoptosis
Sargassaceae
Cells
B-DNA
Cell signaling
Seaweed
NAD ADP-ribosyltransferase
therapeutics
Poly(ADP-ribose) Polymerases
Caspase 9
Caspase 8
tumor necrosis factors

Keywords

  • Apoptosis
  • Fucoidan
  • NFκB
  • p53
  • Pancreatic cancer
  • Sargassaceae
  • Turbinaria conoides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Plant Science
  • Horticulture

Cite this

Delma, C. R., Thirugnanasambandan, S., Srinivasan, G. P., Raviprakash, N., Manna, S. K., Natarajan, M., & Aravindan, N. (2019). Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53 – NFκB crosstalk. Phytochemistry, 167, [112078]. https://doi.org/10.1016/j.phytochem.2019.112078

Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53 – NFκB crosstalk. / Delma, Caroline R.; Thirugnanasambandan, Somasundaram; Srinivasan, Guru Prasad; Raviprakash, Nune; Manna, Sunil K.; Natarajan, Mohan; Aravindan, Natarajan.

In: Phytochemistry, Vol. 167, 112078, 01.11.2019.

Research output: Contribution to journalArticle

Delma, CR, Thirugnanasambandan, S, Srinivasan, GP, Raviprakash, N, Manna, SK, Natarajan, M & Aravindan, N 2019, 'Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53 – NFκB crosstalk', Phytochemistry, vol. 167, 112078. https://doi.org/10.1016/j.phytochem.2019.112078
Delma CR, Thirugnanasambandan S, Srinivasan GP, Raviprakash N, Manna SK, Natarajan M et al. Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53 – NFκB crosstalk. Phytochemistry. 2019 Nov 1;167. 112078. https://doi.org/10.1016/j.phytochem.2019.112078
Delma, Caroline R. ; Thirugnanasambandan, Somasundaram ; Srinivasan, Guru Prasad ; Raviprakash, Nune ; Manna, Sunil K. ; Natarajan, Mohan ; Aravindan, Natarajan. / Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53 – NFκB crosstalk. In: Phytochemistry. 2019 ; Vol. 167.
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abstract = "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 NFκB 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) K{\"u}tzing (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 κB (NFκB) 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-α (TNFα)-mediated NFκB DNA-binding activity in PC cells. Upregulation of cytoplasmic IκB levels and significant reduction of NFκB-dependent luciferase activity further substantiate the inhibitory potential of seaweed fucoidans on NFκB. Moreover, fucoidan(s) treatment increased cellular p53 in PC cells and reverted NFκB forced-expression-related p53 reduction. The results suggest that fucoidan regulates PC progression and that fucoidans may target p53–NFκB crosstalk and dictate apoptosis in PC cells.",
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