Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways

Duesbery, Nicholas S.; Resau, James H.; Webb, Craig P.; Koochekpour, Shahriar; Koo, Han Mo; Leppla, Stephen H.; Woude, George F. Vande

doi:10.1073/pnas.061031898

Cited by 87 publications

(86 citation statements)

References 42 publications

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“…Conceivably, a combination of a small molecule MAPK inhibitor coupled with a neutralizing anti-VEGF therapy might be effective. Note that tumor lethal factor (TLF), the anthrax lethal toxin, has been shown to be a potent MAPK inhibitor (37) and also dramatically suppresses tumor angiogenesis (38). The mechanisms underlying the inhibition of tumor angiogenesis by TLF is not clear, but it is possible that TLF can increase the expression of the antiangiogenic factor TSP1 from tumor cells while decreasing VEGF.…”

Section: Resultsmentioning

confidence: 99%

Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation

Zhang

Volpert

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

323

242

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Hepatocyte growth factor͞scatter factor (HGF͞SF), acting through the Met receptor, plays an important role in most human solid tumors, and inappropriate expression of this ligand-receptor pair is often associated with poor prognosis. The molecular basis for the malignant potential of the HGF͞SF-Met signal in cancer cells has mostly been attributed to its mitogenic and invasive properties. However, HGF͞SF also induces angiogenesis, but the signaling mechanism has not been fully explained, nor has this activity been directly associated with HGF͞SF-Met-mediated tumorigenesis. It is known that HGF͞SF induces in vitro expression of vascular endothelial growth factor (VEGF), a key agonist of tumor angiogenesis; by contrast, thrombospondin 1 (TSP-1) is a negative regulator of angiogenesis. Here, we show that, in the very same tumor cells, in addition to inducing VEGF expression, HGF͞SF dramatically downregulates TSP-1 expression. We show that TSP-1 shut-off plays an important, extrinsic role in HGF͞SF-mediated tumor development, because ectopic expression of TSP-1 markedly inhibits tumor formation through the suppression of angiogenesis. Interestingly, although VEGF-induced expression is sensitive to inhibitors of several pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, and signal transducer and activator of transcription 3, TSP-1 shut-off by HGF͞SF is prevented solely by inhibiting mitogen-activated protein kinase activation. These studies identify HGF͞SF as a key switch for turning on angiogenesis. They suggest that TSP-1 is a useful antagonist to tumor angiogenesis and that it may have therapeutic value when used in conjunction with inhibitors of VEGF.

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Section: Resultsmentioning

confidence: 99%

Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation

Zhang

Volpert

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

323

242

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“…MEKtargeted treatment has been studied in colon, pancreatic, breast or melanoma tumors (Sebolt-Leopold et al, 1999;Duesbery et al, 2001;Yeh et al, 2007;Haass et al, 2008) and recently in human HCC tumors (Klein et al, 2006). Targeting MEK with PD184161, which has the obvious advantages of solubility and oral bioavailability, in vivo resulted in a significant delay in HCC tumor engraftment and inhibition of early tumor growth.…”

Section: Discussionmentioning

confidence: 99%

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

et al. 2008

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The MAPK MEK/ERK pathway is often upregulated in cancer cells and represents an attractive target for development of anticancer drugs. Only few data concerning the specific functions of ERK1 and 2 are reported in the literature. In this report, we investigated the specific role of ERK1 and 2 in liver tumor growth both in vitro and in vivo. DNA synthesis and cells in S phase analysed by flow cytometry, correlated with strong inhibition of Cdk1 and cyclin E levels, are strongly reduced after exposure to the MEK inhibitor, U0126. We obtained a significant reduction of colony formation in soft agar assays and a reduction in the size of tumor xenografts in nude mice treated with U0126. Then, we could specifically abolished ERK1 or 2 expression by small-interfering RNA (siRNA) and demonstrated that ERK2 knockdown but not ERK1 interferes with the process of replication. Moreover, we found that colony formation and tumor growth in vivo were significantly inhibited by targeting ERK2 using stable chemically modified siRNA. Taken together, our results emphasize the importance of the MEK/ERK pathway in liver cancer cell growth in vitro and in vivo and argue for a crucial role of ERK2 in this regulation.

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“…Insight into their in vivo functions may be inferred from the effects of MKK inhibitors upon tumor vascularization. For example, anthrax lethal factor, a protease that inactivates MEK1 and 2 (Duesbery et al, 1998) as well as MKK 3, 4, 6, and 7 (Vitale et al, 2000), substantially inhibits vascularization in mouse xenograft studies (Duesbery et al, 2001). Its antiendothelial effects result not only from its ability to inhibit MKK signaling but also from the upregulation of anthrax toxin receptors in tumor-associated endothelium (St Croix et al, 2000;Bradley et al, 2001).…”

Section: Mkk Signaling and Tumor Vascularizationmentioning

confidence: 99%

MKK signaling and vascularization

et al. 2007

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In 1998, George Vande Woude's lab discovered that anthrax lethal factor (LF), the principal virulence component of anthrax toxin, was a zinc-metalloprotease that cleaved and inactivated mitogen-activated protein kinase kinases (MKK). It was perhaps not surprising, given the known roles of MKK1 and 2 in cell proliferation, that LF was subsequently found to dramatically inhibit tumor growth in vivo. What was not anticipated, however, was that the tumors treated with LF would have a substantially reduced vascular content. This intriguing result was one of the first indications that MKK signaling plays an important role in promoting tumor vascularization in vivo. In the following short review, we will compare in vitro and in vivo evidence that supports the hypothesis that MKK signaling pathways are essential for vascularization.

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Suppression of ras-mediated transformation and inhibition of tumor growth and angiogenesis by anthrax lethal factor, a proteolytic inhibitor of multiple MEK pathways

Cited by 87 publications

References 42 publications

Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation

Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation

RNAi-mediated ERK2 knockdown inhibits growth of tumor cells in vitro and in vivo

MKK signaling and vascularization

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