Manumycin inhibits cell proliferation and the Ras signal transduction pathway in human hepatocellular carcinoma cells

Zhou, Jun; Zhu, Xiao Feng; Pan, Qi; Liao, Di; Li, Zhi Ming; Liu, Zong Chao

doi:10.3892/ijmm.11.6.767

Cited by 10 publications

(14 citation statements)

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“…Activated ERK phosphorylates a number of cytoplasmic and nuclear targets, including transcription factors that mediate growth factor-regulated gene expression. Therefore, activation of ERK, which is a key component in the transduction of one of the signals leading to growth and transformation in many cell types, is mainly caused by Raf-1 (29,42). Consistent with the downregulation of Raf-1, ERK phosphorylation was blocked in response to oridonin, suggesting that oridonin-induced decreased expression of Raf-1 might result in downregulation of phosphorylated ERK.…”

Section: Discussionsupporting

confidence: 54%

“…Upon activation by Raf, MEK can in turn phosphorylate and activate ERK. Therefore, ERK activation is required for cellular transformation induced by oncogenic Ras and Raf (29). We found that after oridonin treatment, the expression of phosphorylated ERK was decreased in a time-dependent manner, while ERK expression did not change, suggesting that oridonin-induced downregulation of Raf-1 might block ERK-activation in A431 cells (Fig.…”

Section: Downregulation Of Raf-1 and Erk In Oridonin-treated A431 Cellsmentioning

confidence: 62%

“…Inactivation of Ras leads to inhibition of human carcinoma cell proliferation by blocking the Ras signal transduction pathway and reduced the expression levels of functional Ras (29). Manumycin A, an antibiotic, can inhibit Ras activity by preventing farnesylation and membrane translocation of Ras.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that Ras does not function unless it is attached to the inside of the cell membrane and inhibition of Ras activity might be related to the downregulation of Ras protein levels (29,38). In the present study, it was found that the expression of Ras protein was decreased in oridonin-treated A431 cells.…”

Section: Discussionmentioning

confidence: 99%

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Oridonin-Induced A431 Cell Apoptosis Partially Through Blockage of the Ras/Raf/ERK Signal Pathway

Li-jun

Tashiro

et al. 2007

J Pharmacol Sci

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Abstract. We have reported that oridonin, a diterpenoid isolated from the plant Rabdosia rubescens, had apoptosis-inducing activities in many cell lines (e.g., human melanoma A375-S2, human cervical cancer HeLa, human breast adenocarcinoma MCF-7, and murine fibrosarcoma L929). In this study, we further investigated signaling events involved in oridonin-induced apoptosis in human epidermoid carcinoma A431 cells. It was found that the total tyrosine kinase activity was inhibited and the protein expressions of epidermal growth factor receptor (EGFR) and phosphorylated EGFR were decreased in oridonin-induced A431 cell apoptosis. Expression of EGFR downstream effector proteins, Grb2, Ras, Raf-1, and extracellular signal-regulated kinase (ERK), was also downregulated by oridonin. Moreover, the oridonin-induced apoptosis was augmented by the Ras inhibitor manumycin A, Raf-1 inhibitor GW5074, or ERK inhibitor PD98059, suggesting that inactivation of Ras, Raf, or ERK participates in oridonin-induced apoptosis. Taken together, oridonin-induced apoptosis in A431 cells might be through blocking EGFR and its downstream Ras / Raf/ ERK signal pathway.

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Section: Discussionsupporting

confidence: 54%

Section: Downregulation Of Raf-1 and Erk In Oridonin-treated A431 Cellsmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Oridonin-Induced A431 Cell Apoptosis Partially Through Blockage of the Ras/Raf/ERK Signal Pathway

Li-jun

Tashiro

et al. 2007

J Pharmacol Sci

View full text Add to dashboard Cite

show abstract

“…Manumycin A is an antibiotic produced by Streptomyces parvulus and is one of the most studied, which has shown both in vitro cytotoxic activity against several cell lines (human pancreatic tumor, thyroid carcinoma, leukemias, myeloma and hepatocellular carcinoma) and in vivo against human cancer xenografted models (pancreatic cancer and thyroid cancer). [100][101][102][103][104][105][106][107] A combined treatment with Manumycin and Paclitaxel (a mitotic inhibitor used in cancer chemotherapy), had a synergistic cytotoxic effect on anaplastic thyroid carcinoma cells. 107 Angiogenesis and Vascular Endothelial Growth Factor are also inhibited by this combination, showing higher cytotoxic effects than when used singly.…”

mentioning

confidence: 99%