| Summary: | 碩士 === 國立中興大學 === 生命科學系所 === 100 === Nasopharyngeal carcinoma (NPC) is a malignancy that arises from the epithelium of the nasopharynx, with poor prognosis even using radiation therapy and chemotherapy. Accordingly, a better therapeutic strategy is certainly needed. 2-(2-fluorophenyl)-6,7 -methylenedioxyquinolin-4-one (CHM-1) is a compound derived from quinolone. This study shows that the viability of NPC cells is significantly reduced in the form of dose- and time-dependent manner with the treatment of CHM-1. First, there are evidences showing CHM-1 has been inducing accumulation of sub-G1 population, DNA fragmentation, active fragments in caspase-8 and caspase-3, and cleavage of poly (ADP-ribose) polymerase (PARP). Next, it was found that CHM-1 inhibited cell cycle progression of NPC cells and resulted in G2/M-S phase arrest manner. Moreover, CHM-1 treatment led to down-regulation of p53 and p21, up-regulation of cyclin B and cdk-2 and suppression of cleavage of cyclin A. Furthermore, Bcl-2 phosphorylation was observed simultaneously after treatment of CHM-1 and caused a reduction of GRP78 expression and suppression of Akt activation. In search of molecular mechanisms underlying CHM-1-mediated NPC cells death, it was found that S phase thymidine-synchronized NPC cells are more susceptible to CHM-1, causing cells death and phosphorylation of Bcl-2. Ectopic expression of wild type PI3-K p85α and ∆ PI3-K p85α show that overexpression of PI3-K/Akt pathway was able to abrogating anti-proliferative activity of CHM-1. In the addition, by using sucrose density-based membrane flotation technique, those results demonstrated that CHM-1 was capable of suppressing Akt activation, resulting in disturbed the protein expression level of PI3-K/Akt on the lipid raft. Thus, results from the study indicate that depletion of the protein expression level of PI3-K/Akt on the lipid raft, enhancement of phosphorylation of Bcl-2 and inhibition of the expression of GRP78 were associated in the CHM-1-induced cell apoptosis of NPC cells.
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