Oridonin induces apoptosis and autophagy in murine fibrosarcoma L929 cells partly via NO-ERK-p53 positive-feedback loop signaling pathway

Yuan-chao Ye, Hong-ju Wang, Lei Xu, Wei-wei Liu, Bin-bin Liu, Shin-Ichi Tashiro, Satoshi Onodera, Takashi Ikejima
Acta Pharmacologica Sinica 2012, 33 (8): 1055-61

AIM: To investigate the role of nitric oxide (NO) in oridonin-induced apoptosis and autophagy in murine fibrosarcoma L929 cells and the underlying molecular mechanisms.

METHODS: Cell viability was measured using MTT assay. Intracellular NO level, SubG(1) cell ratio and autophagy cell ratios were analyzed with flow cytometry after diaminofluorescein-2 diacetate (DAF-2DA), propidium iodide (PI) and monodansylcadaverine (MDC) staining, respectively. Protein expression was examined using Western blot analysis.

RESULTS: Exposure of L929 cells to oridonin (50 μmol/L) for 24 h led to intracellular NO production. Pretreatment with NOS inhibitor 1400w or L-NAME inhibited oridonin-induced apoptosis and autophagy in L929 cells. The pretreatment decreased the apoptosis-related protein Bax translocation and cytochrome c release, increased Bcl-2 level, reversed the autophagy-associated protein Beclin 1 increase and conversion of LC3 I to LC3 II. Furthermore, pretreatment with NO scavenger DTT completely inhibited oridonin-induced apoptosis and autophagy in L929 cells. In addition, oridonin (50 μmol/L) activated ERK and p53 in L929 cells, and the interruption of ERK and p53 activation by PD 98059, pifithrin-α, or ERK siRNA decreased oridonin-induced apoptosis and autophagy. The inhibition of NO production reduced oridonin-induced ERK and p53 activation, and NO production was down-regulated by blocking ERK and p53 activation.

CONCLUSION: NO played a pivotal role in oridonin-induced apoptosis and autophagy in L929 cells. Taken together with our previous finding that ERK contributes to p53 activation, it appears that NO, ERK, and p53 form a positive feedback loop. Consequently, we suggest that oridonin-induced apoptosis and autophagy are modulated by the NO-ERK-p53 molecular signaling mechanism in L929 cells.

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