Bcl-2 Up-Regulation and P-p53 Down-Regulation Account for the Low Sensitivity of Murine L929 Fibrosarcoma Cells to Oridonin-Induced Apoptosis

Huang, Jian; Li-jun, WU; Tashiro, Shin‐ichi; Onodera, Satoshi; Ikejima, Takashi

doi:10.1248/bpb.28.2068

Cited by 28 publications

(11 citation statements)

References 23 publications

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“…When p38MAPK signaling was inhibited, GPC3 was not able to induce up-regulation of the pro-apoptotic molecules Bax and PUMA, nor could it reduce the levels of the anti-apoptotic Bcl-xL, Bcl-2 and XIAP. The role of p38MAPK pathway in the regulation of apoptotic molecules was previously reported by other authors [36,37], however, this is the first report that demonstrates that GPC3 induces an increase in apoptosis susceptibility of mammary tumor cells through p38MAPK signaling pathway activation and the consequent regulation of Bax, PUMA, Bcl-xL, Bcl-2 and XIAP expression.…”

Section: Discussionmentioning

confidence: 54%

RETRACTED ARTICLE: Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways

Buchanan

Stigliano

Garay-Malpartida

et al. 2009

Breast Cancer Res Treat

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Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. We demonstrated that GPC3 inhibits canonical Wnt signaling, as well as it activates non canonical pathway. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one. We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival.

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Section: Discussionmentioning

confidence: 54%

RETRACTED ARTICLE: Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways

Buchanan

Stigliano

Garay-Malpartida

et al. 2009

Breast Cancer Res Treat

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“…According to our findings, MAPKs activities were profoundly affected by oridonin, ERK activity was inhibited while JNK and P38 kinase activities were provoked, which was consistent with previous data of our studies. [35][36][37][38] However, when autophagy was blocked by 3-MA, both inhibition of ERK and activation of JNK and P38 kinase were reversed, suggesting that oridonin-induced autophagy exerted its synergic effect on apoptosis through MAPKs pathway.…”

Section: )mentioning

confidence: 99%

Autophagy Preceded Apoptosis in Oridonin-Treated Human Breast Cancer MCF-7 Cells

Cui

Tashiro

Onodera

et al. 2007

Biological & Pharmaceutical Bulletin

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123

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Oridonin is extracted and purified from traditional Chinese herbs, Rabdosia rubescens. It is a complicated compound containing diterpenoids and other ingredients. It is also one of the most important traditional Chinese herbs commonly used in clinical treatment nowadays. 1) Oridonin has been studied exclusively in China and has been shown to possess anti-tumor activity against murine sarcoma and leukemia cells. 2,3) Programmed cell death comprises several subtypes, as revealed by morphology. Autophagic cell death or type II programmed cell death is an evolutionary conserved membrane trafficking pathway which mediates the transport of cytosolic materials and superfluous organelles and long-lived proteins to the lysosome and occurs in all eukaryotic cells. 4,5) During autophagy, a cup-shaped structure, the pre-autophagosome, engulfs cytosolic components, including organelles, and closes, forming an autophagosome, which subsequently fuses with a lysosome, leading to the proteolytic degradation of internal components of the autophagosome by lysosomal lytic enzymes.6) The formation of the autophagosome is also dependent upon the enzyme phosphatidylinositol 3-phosphate kinase (class III PI3K) in mammalian cells 7) and its ortholog Vps34 in yeast.8) The first evidence for the implication of this enzyme stemmed from the discovery that 3-methyladenine is able to block the formation of autophagosomes. 9) In vitro studies showed that 3-MA inhibits PI3K activity.7,10) The inhibitory effect of 3-MA on intracellular trafficking of proteins from late endosomes to lysosomes 11) is compatible with the requirement of PI3K at this step. 12)Apoptotic cell death or type I programmed cell death was originally conceived on morphologic grounds, namely describing the condensation of chromatin at the nuclear membrane, prominent condensation of cytoplasm and the fragmentation of cell and nucleus, while organelles were well preserved and autophagocytosis was essentially absent. 13) It has been reported that oridonin was found to induce growth inhibition and apoptosis of human breast cancer cell line 14) and this cell line could be induced autophagy by tamoxifen.15) Therefore, in this study, we further investigated the relationship between apoptosis and autophagy specifically induced by oridonin in MCF-7 cells. MATERIALS AND METHODS MaterialsOridonin was obtained from the Kunming Institute of Botany, The Chinese Academy of Sciences (Kunming, China). Fetal bovine serum (FBS) was purchased from TBD Biotechnology Development (Tianjin, China); Monodansylcadervarine (MDC), 3-methyladenine (3-MA), propidium iodode (PI), P38 inhibitor SB203580, JNK inhibitor SP600125, ERK1/2 inhibitor PD98059, Hoechst 33258 and RNase A were purchased from Sigma Chemical (St. Louis, MO, U.S.A); Thiazolyl blue (MTT) was from Sino-American Biotechnology (Beijing, China); rabbit polyclonal antibodies against JNK, phosphorylated JNK, P38, phosphorylated P38, Bax and Bcl-2; mouse polyclonal antibodies against ERK and phosphorylated ERK, horseradish peroxidase-conjugated...

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“…Oridonin causes apoptosis of cancer cells by inhibiting the activation of NF-κβ, signal transducer and activator of transcription 3 and protein kinase B (Akt) [11] . Oridonin also downregulates the expression of various genes that NF-κβ regulates, including Bcl-2, cyclooxygenase-2 (COX-2), cyclinD1, and adhesion molecules [12] . The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays an important role in various cellular processes including cell growth, survival, and motility [13] .…”

Section: Introductionmentioning

confidence: 99%

Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line

Yang

et al. 2007

Acta Pharmacol Sin

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Aim: To investigate the apoptosis-inducing effect of oridonin, a diterpenoid isolated from Rabdosia rubescens, in the human cervical carcinoma HeLa cell line. Methods: A morphological analysis, nuclear condensation, and fragmentation of chromatin were monitored using Hoechst 33342 staining. Cell viability was assessed using the 3-(4, 5-dimethylthiazol-(2)-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Cell apoptosis and the apoptosis-related activation in the HeLa cell line were evaluated by flow cytometry and Western blotting. Results: Oridonin suppressed the proliferation of the HeLa cell line in a dose-and time-dependent fashion. Oridonin treatment downregulated the activation of protein kinase B (Akt), the expression of forkhead box class O (FOXO) transcription factor, and glycogen synthase kinase 3 (GSK3). Oridonin also induced the release of cytochrome c accompanied by the activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase cleavage. In addition, Z-D(OMe)-E(OMe)-V-D(OMe)-FMK (z-DEVD-fmk), an inhibitor of caspases, prevented caspase-3 activation and abrogated oridonin-induced cell death. Finally, oridonin treatment of the HeLa cell line downregulated the expression of the inhibitor of the apoptosis protein. Conclusion:Our results showed that oridonin-induced apoptosis involved several molecular pathways. Oridonin may suppress constitutively activated targets of phosphatidylinositol 3-kinase (Akt, FOXO, and GSK3) in the HeLa cell line, inhibiting the proliferation and induction of caspase-dependent apoptosis.

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Bcl-2 Up-Regulation and P-p53 Down-Regulation Account for the Low Sensitivity of Murine L929 Fibrosarcoma Cells to Oridonin-Induced Apoptosis

Cited by 28 publications

References 23 publications

RETRACTED ARTICLE: Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways

RETRACTED ARTICLE: Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways

Autophagy Preceded Apoptosis in Oridonin-Treated Human Breast Cancer MCF-7 Cells

Oridonin induces apoptosis via PI3K/Akt pathway in cervical carcinoma HeLa cell line

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