Ilimaquinone, a marine sponge metabolite, displays anticancer activity via GADD153-mediated pathway.
The marine organisms produce many metabolic substances with numerous pharmacological activities. It has been suggested that ilimaquinone, a metabolite of sea sponge, can induce vesiculation of the Golgi apparatus and display several biological activities, such as anti-human immunodeficiency virus, anti-inflammation as well as anti-microbial activities. In this study, the sulforhodamine B assays showed that ilimaquinone induced a concentration-dependent anti-proliferative effect in several types of cancer cell lines, including prostate cancer PC-3 and LNCaP, non-small cell lung cancer A549 and hepatocellular carcinoma Hep3B cells. The anticancer mechanism of ilimaquinone in the representative PC-3 cells was identified. Ilimaquinone induced a time-dependent increase of G(1) phase arrest and a subsequent increase of hypodiploid sub-G(1) phase (apoptosis) of the cell cycle. The arrest of the cell cycle was associated with a sustained high level of nuclear cyclin E but the absence of DNA synthesis by flow cytometric analysis, indicating an incomplete S phase. Although ilimaquinone-induced Golgi vesiculation, the data showed that the inhibition of cancer cell growth was not through the Golgi fragmentation. Several biological kinases and transcription factors were examined in this study. The data demonstrated that ilimaquinone did not activate extracellular signal-regulated kinase and phosphatidylinositol 3-kinase but induce the up-regulation and nuclear translocation of growth arrest and DNA damage inducible gene 153 (CHOP/GADD153). Furthermore, ilimaquinone-mediated anti-proliferative effect is significantly reduced in the antisense CHOP/GADD153-overexpressing cells. Ilimaquinone also inhibited DNA binding of NF-kappaB; however, this inhibitory effect could not explain ilimaquinone-induced anticancer effect. In summary, it is suggested that ilimaquinone induces the anti-proliferative effect through the G(1) arrest of the cell cycle and the up-regulation and nuclear translocation of CHOP/GADD153.
Lu
Pin-Hsuan
PH
School of Pharmacy, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, Taiwan.
Chueh
Shih-Chieh
SC
Kung
Fan-Lu
FL
Pan
Shiow-Lin
SL
Shen
Ya-Ching
YC
Guh
Jih-Hwa
JH
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism; D053492:Elafin / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011161:Porifera / Q000737:chemistry*; D011809:Quinones / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D019927:Cyclin E; C497249:DDIT3 protein, human; D053492:Elafin; D016328:NF-kappa B; C506806:PI3 protein, human; D011809:Quinones; D012717:Sesquiterpenes; D051742:Transcription Factor CHOP; C467077:ilimaquinone; D048049:Extracellular Signal-Regulated MAP Kinases