|Title:||Anti-cancer efficacy of selenium nanoparticles decorated by polysaccharide-protein complex isolated from Pleurotus tuber-regium : cellular uptake and anti-tumor mechanisms on HCT 116 colorectal cancer cells|
|Subject:||Hong Kong Polytechnic University -- Dissertations|
Colon (Anatomy) -- Cancer.
|Department:||Department of Applied Biology and Chemical Technology|
|Pages:||xviii, 144 pages : color illustrations|
|Abstract:||Colorectal cancer (CRC) is one of the major causes of cancer morbidity and mortality in the world, yet current choices for adjuvant therapy are limited due to the suboptimal response rate. Selenium (Se) is an essential trace element to human health. Recently, selenium nanoparticles (SeNP) have become the new research topic, since they were found to possess remarkable anti-cancer efficacy and low toxicity. Although apoptosis induction was found to be the critical cellular event of SeNP-induced anti-tumor activity in vitro, their cell inhibition mechanisms are not fully understood at cellular and molecular levels at present. Besides, for further development of SeNP into a novel anti-tumor agent, information on their cellular uptake behavior is crucial. However, related information is currently very limited. By using a water soluble polysaccharide-protein complex (PSP) isolated from the mushroom Pleurotus tuber-regium (Fr.) Singer, our lab has successfully prepared a highly stable SeNP (PTR-SeNP) under a simple redox system. PTR-SeNP was found to significantly inhibit the growth of human breast carcinoma MCF-7 cells (IC50= 3.7 μM) as well as possess higher stability and lower toxicity towards normal cells. In order to gain a better understanding on the anti-cancer efficacy of PTR-SeNP on CRC, in this project, the in vitro anti-proliferative effect was firstly determined with six human colorectal cancer cell lines (SW1116, SW620, COLO205, HT-29, HCT-15 and HCT 116). Apart from cellular uptake behavior, different cell inhibition mechanisms such as apoptosis, cell cycle arrest and autophagy were then further investigated in the most susceptible human colorectal cancer cell line.|
Among the panel of six different human colorectal cancer cell lines, PTR-SeNP exhibited the highest dose-and time-dependent anti-proliferation effect on the HCT 116 cells with an IC50 value of 4.0 μM. Besides, PTR-SeNP were found to induce dose-and time-dependent apoptosis in the HCT 116 cells (significant increase in phosphatidylserine translocation, DNA fragmentation and sub-G1 population), via a caspase-3 independent pathway. In addition, PTR-SeNP markedly induced G2/M cell cycle arrest after 48 h treatment by down-regulating Cyclin D1 and Cyclin D3 at 12 h, CDK2 and CDK4 at 24 h, and cdc2/CDK1 at 48 h. Considering the role of Cyclin D1 in regulating cell cycle progression and cell proliferation, Cyclin D1 may serve as the primary molecular target of PTR-SeNP induced G2/M cell cycle arrest. Further investigation on autophagy also discovered that PTR-SeNP could induce initiation and completion of autophagic flux in the HCT 116 cells as evidenced by the presence of autophagosomes in EGFP-LC3 plasmid transfected cells, as well as time-dependent increase of autophagy initiators, such as Beclin 1 (peaked at 24 h), LC-3 II (peaked at 24 h) and p62/SQSTM1 (peaked at 12 h) after Western Blot analysis. Last but not least, PTR-SeNP were found to colocalize with both Golgi apparatus and lysosomes in the HCT 116 cells after cellular internalization as early as 2 and 5 min, respectively. It is the first study to discover that SeNPs could colocalize with Golgi apparatus, suggesting the involvement of caveolae-mediated endocytosis. We anticipated that findings of this study would provide significant insights into the development of PTR-SeNP as novel anti-tumor agent for treating CRC.
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