Mechanism of apoptotosis induced by ortho-topolin riboside in human hepatoma cell line SMMC-7721 |
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Authors: | Li Wang Chao Sun Zhen-Hua Wang Guang-Qin Guo |
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Affiliation: | 1. Department of Cell Biology, School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China;2. Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China;3. Graduate University of Chinese Academy of Sciences, Beijing 100000, PR China |
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Abstract: | The naturally occurring cytokinin, ortho-topolin riboside (oTR), has been recently reported to have a strong anticancer effect. However, the molecular mechanism has not been elucidated. From our research we found that oTR strongly inhibited the proliferation of SMMC-7721 cells inducing apoptosis. After oTR treatment, up-regulation of the protein levels of pro-apoptotic Bax and the down-regulation of the anti-apoptotic proteins, Bcl-2 and Bcl-xL was observed, leading to the loss of mitochondrial membrane potential, the release of cytochrome c from the mitochondria into the cytosol, the downstream activation of caspase-9 and caspase-3, as well as the cleavage of poly ADP-ribose-polymerase (PARP), the effect of apoptosis could be blocked by the pan-specific caspase inhibitor z-VAD-fmk and caspase-9-specific inhibitor z-LEHD-fmk. Moreover, oTR was shown to inhibit the activation of the extracellular signal-regulated kinase-1/2 (ERK1/2) as well as the Akt pathway. These results suggest that oTR interferes with the mitogen-activated protein kinase (MAPK) and Akt pathways and induces the apoptosis of human SMMC-7721 cells through the activation of intrinsic mitochondria-mediated pathways. However, the apoptosis was completely prevented when cells were treated with A-134974, an inhibitor of adenosine kinase, it indicated that the intracellular phosphorylation of oTR is necessary for its cytotoxic effects to SMMC-7721 cells. |
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Keywords: | A-134974, N7-[(1&prime R,2&prime S,3&prime R,4&prime S)-2&prime ,3&prime -dihydroxy-4&prime -aminocyclopentyl BAR, N6-benzyladenosine DMSO, dimethyl sulfoxide ERK1/2, extracellular signal-regulated kinase-1/2 iPR, N6-isopentenyladenosine KR, kinetin riboside MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide oTR, ortho-topolin riboside PARP, poly-ADP-ribose-polymerase PMSF, phenylmethanesulfonyl fluoride PI, propidium iodide PBS, phosphate-buffered saline |
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