Pathway Analysis of Fucoidan Activity Using a Yeast Gene Deletion Library Screen

Abstract

Fucoidan, the sulfated fucose-rich polysaccharide derived from brown macroalgae, was reported to display some anti-cancer effects in in vitro and in vivo models that included apoptosis and cell cycle arrest. The proposed mechanisms of action involve enhanced immune surveillance and direct pro-apoptotic effects via the activation of cell signaling pathways that remain largely uncharacterized. This study aimed to identify cellular pathways influenced by fucoidan using an unbiased genetic approach to generate additional insights into the anti-cancer effects of fucoidan. Drug–gene interactions of Undaria pinnatifida fucoidan were assessed by a systematic screen of the entire set of 4,733 halpoid Saccharomyces cerevsiae gene deletion strains. Some of the findings were confirmed using cell cycle analysis and DNA damage detection in non-immortalized human dermal fibroblasts and colon cancer cells. The yeast deletion library screen and subsequent pathway and interactome analysis identified global effects of fucoidan on a wide range of eukaryotic cellular processes, including RNA metabolism, protein synthesis, sorting, targeting and transport, carbohydrate metabolism, mitochondrial maintenance, cell cycle regulation, and DNA damage repair-related pathways. Fucoidan also reduced clonogenic survival, induced DNA damage and G1-arrest in colon cancer cells, while these effects were not observed in non-immortalized human fibroblasts. Our results demonstrate global effects of fucoidan in diverse cellular processes in eukaryotic cells and further our understanding about the inhibitory effect of Undaria pinnatifida fucoidan on the growth of human cancer cells.

Fucoidan Independently Enhances Activity in Human Immune Cells and Has a Cytostatic Effect on Prostate Cancer Cells in the Presence of Nivolumab

“…Interestingly, however, no apoptosis was observed to be induced upon treatments (Figure 4b,d,f), thereby suggesting a potential cytostatic effect of the fucoidans. Cell cycle arrest has previously been noted for UP [28].…”

“…Interestingly, however, no apoptosis was observed to be induced upon treatments (Figure 4b,d,f), thereby suggesting a potential cytostatic effect of the fucoidans. Cell cycle arrest has previously been noted for UP [28]. Apoptosis is represented as an index evaluated with respect to the apoptosis events and cell number in each condition.…”

Micro RNA Expression after Ingestion of Fucoidan; A Clinical Study

“…In this context it is also important to note that our prior research illustrates that cancer cells can respond very differently compared to non-immortalized cells. While UPF effectively induced DNA damage in colorectal cancer cells, it had no effect on non-immortalized primary human skin fibroblasts [4], which could also account for the different miRNA responses observed by the different studies.…”

“…Fucoidans can also inhibit the adhesion of proteins and organisms to non-biological surfaces, and may help to inhibit biofouling [3]. Previous data using a yeast deletion library illustrated that fucoidans can interact with more fundamental cellular pathways than previously anticipated [4]. Not only did the yeast study confirm that cell surface signaling pathways are affected by fucoidan, this study identified many additional fundamental intracellular pathways such as ribosome biogenesis, peroxisome biogenesis, DNA damage repair, cell cycle control and energy metabolism, just to name a few.…”

Therapies from Fucoidan: New Developments

“…Using a systematic screen of the entire set of 4733 haploid Saccharomyces cerevisiae gene deletion strains, an analysis of cell pathways revealed that multiple cellular pathways were affected by exposure to fucoidan extracts, and that cDNA damage and cell cycle arrest occurred in colon cancer cell lines. Normal fibroblasts were unaffected under the same conditions [80]. There were global effects of the fucoidan studied on a wide range of eukaryotic cellular processes, including RNA metabolism, protein synthesis, sorting, targeting and transport, carbohydrate metabolism, mitochondrial maintenance, cell cycle regulation and DNA damage repair-related pathways.…”