Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

Wilson, Thomas J.; Singh, Rakesh K.

doi:10.1016/j.bbcan.2007.11.001

Cited by 43 publications

(58 citation statements)

References 72 publications

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“…Targeting CCL2 with a neutralizing antibody caused prostate tumor regression (24)(25)(26). The list also includes mRNAs encoding the matrix metalloproteinases (MMPs) MMP3 and MMP9, which are overexpressed in PC3 prostate cancer cells (27), and promote invasion and metastasis by rearrangement of the ECM (28,29). Other mRNAs encode the inhibitor of apoptosis, baculoviral IAP repeat-containing protein 2 (BIRC2), and the growth factor VEGFC.…”

Section: Resultsmentioning

confidence: 99%

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Furic

Liang

Larsson

et al. 2010

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

460

566

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Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5′ cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs. PTEN | translational controlA berrations in the control of mRNA translation initiation have been documented in many tumor types (1-4). Translation initiation is controlled in part by eIF4E, the mRNA 5′ cap-binding protein. eIF4E is a proto-oncogene, inasmuch as its overexpression in immortalized rodent fibroblasts or human epithelial cells causes transformation (5, 6), and in mouse models its overexpression engenders tumor formation (7,8). eIF4E is phosphorylated by the MNK1/2 serine/threonine kinases, which are activated in response to mitogenic and stress signaling downstream of ERK1/2 and p38 MAP kinase, respectively (9, 10). eIF4E phosphorylation at serine 209 by MNK1/2 promotes its transformation activity (11,12). To study the role of eIF4E phosphorylation in tumorigenesis in the whole organism, we generated a knock-in (KI) mouse in which eIF4E serine 209 was mutated to alanine. Here, we show that mouse embryonic fibroblasts (MEFs) isolated from eIF4E S209A/S209A embryos display a marked resistance to oncogene-induced transformation. Furthermore, the mutant mice are viable, but are resistant to development of Pten loss-induced prostate cancer, and this resistance is associated with a decrease in MMP3, CCL2, VEGFC, and BIRC2 proteins. Moreover, eIF4E is highly phosphorylated in hormone-refractory prostate cancer, which correlates with poor clinical outcome. These results demonstrate the importance of eIF4E phosphorylation in tumorigenesis and validate the eIF4E phosphorylation pathway as a potential therapeutic target for cancer. ResultsSer209 Is the Only Phosphorylation Site in eIF4E. To address the role of eIF4E phosphorylation in tumorigenesis, a knock-in (KI) mouse in which serine 209 was replaced by an alanine residue was generated. The strategy and targeting vector construction for the generation, selection, and genotyping of the S209A mice is shown in Fig. S1. The eIF4E S...

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Section: Resultsmentioning

confidence: 99%

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Furic

Liang

Larsson

et al. 2010

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

460

566

View full text Add to dashboard Cite

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“…MMP-9 act not only as solubilizers of bone matrix but also as regulators of the initiation of bone resorption [8]. Study has shown that MMP-9 is produced by osteoclast in the human bone tissues and suggest that it can degrade bone collagens in concert with MMP-1 and cysteine proteinases in the subosteoclastic microenvironment [16]. Several studies have been conducted to analyze the MMP-9 expression in ameloblastoma [8,[12][13][14][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase-9 (MMP-9) Expression in Different Subtypes of Ameloblastoma

Anne

Krisnuhoni

Chotimah

et al. 2013

J. Maxillofac. Oral Surg.

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Background Ameloblastoma is a common benign odontogenic tumor of the jaw with a local invasive and highly destructive behavior and can develop in any age, with peak prevalence in 3rd-4th decade. Ameloblastoma can be divided into six histological types: follicular, plexiform, acanthomatous, desmoplastic, granular, and basal cell. Matrix metalloproteinase-9 (MMP-9) (92-kD gelatinase/ type IV collagenases = gelatinase B) is involved in bone resorption by degradation of extracellular matrix and osteoclasts recruitment. Recent studies have found that MMP-9 is expressed by ameloblastoma and has a role in ameloblastoma local invasiveness. Objective To analyze MMP-9 expression between different histological types of ameloblastoma. Material and Method Forty samples of ameloblastoma were collected through consecutive sampling and the MMP-9 expression was detected using immunohistochemistry. Result All samples showed positive MMP-9 expression with moderate to strong intensity. 82.4 % plexiform type and 83.3 % mixed type have strong immunoexpression, significantly different with follicular type with only 36.4 % (P \ 0.05). Conclusion Ameloblastoma plexiform and mixed type have higher MMP-9 expression than ameloblastoma follicular type. Different MMP-9 expression may contribute in different ameloblastoma biological behavior.

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“…Although high protease activities are found in many solid tumors, 37 the use of a stringent assay of calpastatin degradation and the limiting of our analysis to HCCs arising on noncirrhotic livers allowed us to correlate calpain activation with a Bid decrease in human HCC. Although more clinical samples need to be analyzed to substantiate our interpretation, these data are consistent with the idea that the activation of calpains by HCV and its consequences on the apoptotic signaling pathways, observed in several animal and cellular models, are also relevant to human pathology.…”

Section: Discussionmentioning

confidence: 99%

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway

et al. 2009

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An unresolved question regarding the physiopathology of hepatitis C virus (HCV) infection is the remarkable efficiency with which host defenses are neutralized to establish chronic infection. Modulation of an apoptotic response is one strategy used by viruses to escape immune surveillance. We previously showed that HCV proteins down-regulate expression of BH3-only Bcl2 interacting domain (Bid) in hepatocytes of HCV transgenic mice. As a consequence, cells acquire resistance to Fas-mediated apoptosis, which in turn leads to increased persistence of experimental viral infections in vivo. This mechanism might participate in the establishment of chronic infections and the resulting pathologies, including hepatocellular carcinoma. We now report that Bid is also down-regulated in patients in the context of noncirrhotic HCV-linked tumorigenesis and in the HCV RNA replicon system. We show that the nonstructural HCV viral protein NS5A is sufficient to activate a calpain cysteine protease, leading to degradation of Bid. Moreover, pharmacological inhibitors of calpains restore both the physiological levels of Bid and the sensitivity of cells toward a death receptor-mediated apoptotic signal. Finally, human HCV-related tumors and hepatocytes from HCV transgenic mice that display low Bid expression contain activated calpains. Conclusion: Calpains activated by HCV proteins degrade Bid and thus dampen apoptotic signaling. These results suggest that inhibiting calpains could lead to an improved efficiency of immune-mediated elimination of HCV-infected cells. (HEPATOLOGY 2009;50:1370-1379.)P ersistent infection with hepatitis C virus (HCV) is among the most common infectious causes of chronic liver disease. The majority of patients fail to clear the virus and become chronic carriers, with a persistent presence of detectable virus in the serum. 1 Patients with chronic hepatitis C are at risk for hepatic fibrosis, frequently culminating in hepatic cirrhosis and hepatocellular carcinoma (HCC). 2 FL-N/35 transgenic mice, with hepatocyte-targeted expression of the entire open reading frame of the genotype 1b HCV, are at risk for steatosis and hepatocellular adenoma and carcinoma. 3 We previously showed that the FL-N/35 hepatocytes are resistant to apoptosis induced by the Fas/CD95 death receptor stimulation. The lack of sensitivity to apoptotic stimulation was related to decreased expression of BH3-only Bcl2 interacting domain (Bid), a BH3-only member of the Bcl-2 family of apoptosis regulators. 4 Importantly, Bid-deficient hepatocytes are refractory to T lymphocyte-induced cell death, suggesting that apoptosis contributes to HCV persistence and, as a consequence, to liver pathologies characteristic of chronic HCV infection. 4 Here, we report that Bid is also down-regulated in the context of the subgenomic and genome-length HCV replicons and in a subset of HCV-linked human HCC.

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Proteases as modulators of tumor–stromal interaction: Primary tumors to bone metastases

Cited by 43 publications

References 72 publications

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression

Matrix Metalloproteinase-9 (MMP-9) Expression in Different Subtypes of Ameloblastoma

Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway

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