Involvement of JNK-initiated p53 accumulation and phosphorylation of p53 in pseudolaric acid B induced cell death

Gong, Xianfeng; Wang, Minwei; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1038/emm.2006.50

Cited by 30 publications

(21 citation statements)

References 23 publications

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“…Bax and p53 was upregulated by proton beam (data not shown), sug-gesting that p53 increased cell death through the transcription-dependent apoptotic mechanism in LLC cells. Usually p53 activates caspases by the mitochondrial pathways (Schuler and Green, 2001;Kadenbach et al, 2004;Gong et al, 2006) or alternatively by generation of ROS (Polyak et al, 1997;Li et al, 1999). From our results, proton beam activates caspase-3 as well as increased oxidative stress.…”

Section: Discussionmentioning

confidence: 53%

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Lee

Park

et al. 2008

Exp Mol Med

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Proton beam is useful to target tumor tissue sparing normal cells by allowing precise dose only into tumor cells. However, the cellular and molecular mechanisms by which proton beam induces tumor cell death are still undefined. We irradiated three different tumor cells (LLC, HepG2, and Molt-4) with low energy proton beam (35 MeV) with spread out Bragg peak (SOBP) in vitro, and investigated cell death by MTT or CCK-8 assay at 24 h after irradiation. LLC and HepG2 cells were sensitive to proton beam at over 10 Gy to induce apoptosis whereas Molt-4 showed rather low sensitivity. Relative biological effectiveness (RBE) values for the death rate relative to γ-ray were ranged from 1.1 to 2.3 in LLC and HepG2 but from 0.3 to 0.7 in Molt-4 at 11 d after irradiation by colony formation assay. The typical apoptotic nuclear DNA morphological pattern was observed by staining with 4'-6-diamidino-2-phenylindole (DAPI). Tiny fragmented DNA was observed in HepG2 but not in Molt-4 by the treatment of proton in apoptotic DNA fragment assay. By FACS analysis after stained with FITC-Annexin-V, early as well as median apoptotic fractions were clearly increased by proton treatment. Proton beam-irradiated tumor cells induced a cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) and procaspases-3 and -9. Activity of caspases was highly enhanced after proton beam irradiation. Reactive oxygen species (ROS) were significantly increased and N-acetyl cysteine pretreatment restored the apoptotic cell death induced by proton beam. Furthermore, p38 and JNK but not ERK were activated by proton and dominant negative mutants of p38 and JNK revived proton-induced apoptosis, suggesting that p38 and JNK pathways may be activated through ROS to activate apoptosis. In conclusion, our data clearly showed that single treatment of low energy proton beam with SOBP increased ROS and induced cell death of solid tumor cells (LLC and HepG2) in an apoptotic cell death program by the induction of caspases activities.

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Section: Discussionmentioning

confidence: 53%

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Lee

Park

et al. 2008

Exp Mol Med

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“…PAB exerts potent antifungal, antimicrobial [1] , antifertility [2,3] , and cytotoxic activity in vitro [4] , and the mechanisms of PAB-induced cell death in human myelocytic leukemia K562, human cervical carcinoma HeLa, and human melanoma A375-S2 in vitro have been reported [5][6][7] . However, the mechanism of PAB-induced cell death in human breast cancer MCF-7 is not clear.…”

Section: Introductionmentioning

confidence: 99%

Pseudolaric acid B induces apoptosis, senescence, and mitotic arrest in human breast cancer MCF-7

Yu¹,

Cui

Jiang

et al. 2007

Acta Pharmacologica Sinica

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Aim: The aim of the present study was to investigate the inhibitory effect of pseudolaric acid B (PAB) on human breast cancer MCF-7 cells. Methods: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, morphological changes, acridine orange staining, and agarose gel electrophoresis were applied to detect apoptosis. The percentage of apoptotic and necrotic cells was calculated by the lactate dehydrogenase activity-based cytotoxicity assay; senescence associated (SA)-β-galactosidase activity was detected to evaluate senescence; flow cytometric analysis of propidium iodide staining was carried out to investigate the distribution of cell cycle, and the protein expression was examined by Western blot analysis. Results: During apoptosis, the half maximal inhibitory concentration IC 50 was 3.4 and 1.35 µmol/L at 36 and 48 h after PAB treatment, respectively. The MCF-7 cells exposed to PAB showed typical characteristics of apoptosis, including the morphological changes and DNA fragmentation. The MCF-7 cells treated with 4 µmol/L PAB for 36 h underwent apoptosis, but not necrosis. The apoptosis induced by PAB was independent of the death receptor pathway. The senescent cells became larger and flatter, and the SA-β-galactosidase staining was positive. PAB induced obvious mitotic arrest and it preceded apoptosis and senescence. The expressions of p21 and p53 was upregulated with PAB treatment, and cyclin B1 was upregulated and transported from the cytoplasm to nuclei, and sustained stable levels. Conclusion: PAB induced mitotic arrest in the MCF-7 cells and inhibited proliferation through apoptosis and senescence. The apoptosis was independent of the death receptor pathway.

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“…PAB is a diterpene acid isolated from the root and trunk bark of Pseudolarix kaempferi and possesses multiple biological and pharmacological activities, including antifungal, antimicrobial, antifertility and antiangiogenic properties (10)(11)(12)(13)(14)(15). It has been previously confirmed that PAB exhibits an antitumor effect by inducing apoptosis in various types of cancer (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Apoptosis is important in homeostasis maintenance through a balance between cell proliferation and cell death (28).…”

Section: Discussionmentioning

confidence: 99%

“…In human HeLa cervical carcinoma cells, PAB promotes apoptosis via activating c-Jun N-terminal kinases (JNK), protein kinase C (PKC) and caspase-3, downregulating extracellular signal-regulated kinases (ERK) and Bcl-2 as well as upregulates the P53 and Bax proteins (16,17). In human melanoma A375-S2 cells, PAB inhibits proliferation and induces apoptosis by arresting the cell cycle at the G2/M checkpoint, upregulating P53 and Bax levels and downregulating expression of Bcl-2 and Bcl-xl proteins (18).…”

Section: Introductionmentioning

confidence: 99%

Role of pseudolaric acid B in A549 lung cancer cell proliferation and apoptosis

Guan

Yang

2013

Molecular Medicine Reports

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Abstract. Recently, traditional Chinese medicine has gained attention for its potential use as a chemotherapeutic agent. Pseudolaric acid B (PAB) is a diterpene acid isolated from Pseudolarix kaempferi and possesses antifungal, antimicrobial, antifertility and antiangiogenic properties. It was also reported that PAB may inhibit proliferation and induce apoptosis in various types of cancer. However, its effects on A549 lung cancer cells remain to be determined. The present study aimed to determine the potential roles of PAB in the proliferation and apoptosis of A549 cells. The results showed that PAB inhibited A549 cell proliferation in a time-and dose-dependent manner. Fluorescence microscopy results showed that cells treated with 20 µmol/l PAB for 24 h exhibited karyorrhexis and apoptotic body formation. In addition, A549 cells were treated with 5, 10, 20, 40 or 80 µmol/l PAB for 24 h and apoptosis was analyzed using Annexin-V/propidium iodide kit. The apoptosis rates were 8. 95, 18.71, 24.66, 35.02 and 43.64%, respectively, in PAB-treated cells and 0.80% in the control group. Furthermore, western blot analysis showed that PAB treatment upregulated the protein levels of Bax, Bad and downregulated Bcl-2 and Bcl-xl expression. In conclusion, PAB may serve as a potent chemotherapeutic agent against human lung cancer.

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Involvement of JNK-initiated p53 accumulation and phosphorylation of p53 in pseudolaric acid B induced cell death

Cited by 30 publications

References 23 publications

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases

Pseudolaric acid B induces apoptosis, senescence, and mitotic arrest in human breast cancer MCF-7

Role of pseudolaric acid B in A549 lung cancer cell proliferation and apoptosis

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