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YangZheng XiaoJi exerts anti-tumour growth effects by antagonising the effects of HGF and its receptor, cMET, in human lung cancer cells.

Jiang WG, Ye L, Ruge F, Owen S, Martin T, Sun PH, Sanders AJ, Lane J, Satherley L, Weeks HP, Gao Y, Wei C, Wu Y, Mason MD - J Transl Med (2015)

Bottom Line: In vivo, YZXJ reduced the rate of tumour growth and potentiated the effects of PHA665752 on tumour growth.It was further revealed that YZXJ significantly reduced the degree of phosphorylation of the HGF receptor in lung tumours.This effect is likely attributed to the inhibition of the HGF receptor activation.

View Article: PubMed Central - PubMed

Affiliation: Cardiff University-Peking University Cancer Institute, Cardiff University School of Medicine, Henry Wellcome Building, Heath Park, Cardiff, CF14 4XN, UK. jiangw@cf.ac.uk.

ABSTRACT

Background: Hepatocyte growth factor (HGF) is a cytokine that has a profound effect on cancer cells by stimulating migration and invasion and acting as an angiogenic factor. In lung cancer, the factor also plays a pivotal role and is linked to a poor outcome in patients. In particular, HGF is known to work in combination with EGF on lung cancer cells. In the present study, we investigated the effect of a traditional Chinese medicine reported in cancer therapies, namely YangZheng XiaoJi (YZXJ) on lung cancer and on HGF mediated migration and invasion of lung cancer cells.

Methods: Human lung cancer cells, SKMES1 and A549 were used in the study. An extract from the medicine was used. Cell migration was investigated using the EVOS and by ECIS. Cell-matrix adhesion and in vitro invasion were assessed. In vivo growth of lung cancer was tested using an in vivo xenograft tumour model and activation of the HGF receptor in lung tumours by an immunofluorescence method.

Results: Both lung cancer cells increased their migration in response to HGF and responded to YZXJ by reducing their speed of migration. YZXJ markedly reduced the migration and in vitro invasiveness induced by HGF. It worked synergistically with PHA665752 and SU11274, HGF receptor inhibitors on the lung cancer cells both on HGF receptor activation and on cell functions. A combination of HGF and EGF resulted in a greater increase in cell migration, which was similarly inhibited by YZXJ, and in combination with the HGF receptor and EGF receptor inhibitors. In vivo, YZXJ reduced the rate of tumour growth and potentiated the effects of PHA665752 on tumour growth. It was further revealed that YZXJ significantly reduced the degree of phosphorylation of the HGF receptor in lung tumours.

Conclusion: YZXJ has a significant role in reducing the migration, invasion and in vivo tumour growth of lung cancer and acts to inhibit the migratory and invasive effects induced by HGF and indeed by HGF/EGF. This effect is likely attributed to the inhibition of the HGF receptor activation. These results indicate that YZXJ has a therapeutic role in lung cancer and that combined strategy with methods to block HGF and EGF should be considered.

No MeSH data available.


Related in: MedlinePlus

YangZheng XiaoJi had an inhibitory effect on the activation of the HGF receptor, cMET in lung cancer cell, A549. Top images from immunoblot assay. The phospho-MET (pMET), total MET (cMET) and the loading control GAPDH were probed with the respective antibodies. Bottom the pMET/cMET band density ratio for the immunoblots. The medicinal extract, DME25 was used at 1:1000 and cMET small inhibitor PHA665752 at 10 nM. Positive control for protein tyrosine phosphorylation was sodium orthovanadate (100 µM) with hydrogen peroxide (0.1 %). In quiescent cells, the limited activation of pMET was marked reduced by DME25, PHA665752 and the combination as indicated by asterisk. HGF caused marked action of the receptor (p < 0.01). The HGF induced activation was significantly inhibited by the DME25/PHA665752 combination (asterisk), however only marginally by DME25 alone (ap = 0.13 vs with HGF only) and PHA665752 (bp = 0.14, vs with HGF only)
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Fig5: YangZheng XiaoJi had an inhibitory effect on the activation of the HGF receptor, cMET in lung cancer cell, A549. Top images from immunoblot assay. The phospho-MET (pMET), total MET (cMET) and the loading control GAPDH were probed with the respective antibodies. Bottom the pMET/cMET band density ratio for the immunoblots. The medicinal extract, DME25 was used at 1:1000 and cMET small inhibitor PHA665752 at 10 nM. Positive control for protein tyrosine phosphorylation was sodium orthovanadate (100 µM) with hydrogen peroxide (0.1 %). In quiescent cells, the limited activation of pMET was marked reduced by DME25, PHA665752 and the combination as indicated by asterisk. HGF caused marked action of the receptor (p < 0.01). The HGF induced activation was significantly inhibited by the DME25/PHA665752 combination (asterisk), however only marginally by DME25 alone (ap = 0.13 vs with HGF only) and PHA665752 (bp = 0.14, vs with HGF only)

Mentions: The effect of YangZheng XiaoJi extract was further evaluated, directly or in combination with cMET small inhibitor PHA665752, on the action of the HGF receptor. In quiescent cells (4 h after serum hunger, only traceable amounts of pMET was detected in control cells (Fig. 5, top), which was significantly inhibited by DME25, PHA665752 and their combination (Fig. 5, top) (p < 0.01 vs control, Fig. 5, bottom). HGF resulted in a marked activation of the receptor (p < 0.01 vs without HGF control) (Fig. 5, bottom). Neither PHA665752 nor DME25 alone exhibited significant inhibition on the HGF activation of its receptor (p > 0.05). However, it was very interesting to note that the combination of PHA665752 and DME25 resulted in a significant inhibition in HGF-induced receptor phosphorylation (Fig. 5).Fig. 5


YangZheng XiaoJi exerts anti-tumour growth effects by antagonising the effects of HGF and its receptor, cMET, in human lung cancer cells.

Jiang WG, Ye L, Ruge F, Owen S, Martin T, Sun PH, Sanders AJ, Lane J, Satherley L, Weeks HP, Gao Y, Wei C, Wu Y, Mason MD - J Transl Med (2015)

YangZheng XiaoJi had an inhibitory effect on the activation of the HGF receptor, cMET in lung cancer cell, A549. Top images from immunoblot assay. The phospho-MET (pMET), total MET (cMET) and the loading control GAPDH were probed with the respective antibodies. Bottom the pMET/cMET band density ratio for the immunoblots. The medicinal extract, DME25 was used at 1:1000 and cMET small inhibitor PHA665752 at 10 nM. Positive control for protein tyrosine phosphorylation was sodium orthovanadate (100 µM) with hydrogen peroxide (0.1 %). In quiescent cells, the limited activation of pMET was marked reduced by DME25, PHA665752 and the combination as indicated by asterisk. HGF caused marked action of the receptor (p < 0.01). The HGF induced activation was significantly inhibited by the DME25/PHA665752 combination (asterisk), however only marginally by DME25 alone (ap = 0.13 vs with HGF only) and PHA665752 (bp = 0.14, vs with HGF only)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4551384&req=5

Fig5: YangZheng XiaoJi had an inhibitory effect on the activation of the HGF receptor, cMET in lung cancer cell, A549. Top images from immunoblot assay. The phospho-MET (pMET), total MET (cMET) and the loading control GAPDH were probed with the respective antibodies. Bottom the pMET/cMET band density ratio for the immunoblots. The medicinal extract, DME25 was used at 1:1000 and cMET small inhibitor PHA665752 at 10 nM. Positive control for protein tyrosine phosphorylation was sodium orthovanadate (100 µM) with hydrogen peroxide (0.1 %). In quiescent cells, the limited activation of pMET was marked reduced by DME25, PHA665752 and the combination as indicated by asterisk. HGF caused marked action of the receptor (p < 0.01). The HGF induced activation was significantly inhibited by the DME25/PHA665752 combination (asterisk), however only marginally by DME25 alone (ap = 0.13 vs with HGF only) and PHA665752 (bp = 0.14, vs with HGF only)
Mentions: The effect of YangZheng XiaoJi extract was further evaluated, directly or in combination with cMET small inhibitor PHA665752, on the action of the HGF receptor. In quiescent cells (4 h after serum hunger, only traceable amounts of pMET was detected in control cells (Fig. 5, top), which was significantly inhibited by DME25, PHA665752 and their combination (Fig. 5, top) (p < 0.01 vs control, Fig. 5, bottom). HGF resulted in a marked activation of the receptor (p < 0.01 vs without HGF control) (Fig. 5, bottom). Neither PHA665752 nor DME25 alone exhibited significant inhibition on the HGF activation of its receptor (p > 0.05). However, it was very interesting to note that the combination of PHA665752 and DME25 resulted in a significant inhibition in HGF-induced receptor phosphorylation (Fig. 5).Fig. 5

Bottom Line: In vivo, YZXJ reduced the rate of tumour growth and potentiated the effects of PHA665752 on tumour growth.It was further revealed that YZXJ significantly reduced the degree of phosphorylation of the HGF receptor in lung tumours.This effect is likely attributed to the inhibition of the HGF receptor activation.

View Article: PubMed Central - PubMed

Affiliation: Cardiff University-Peking University Cancer Institute, Cardiff University School of Medicine, Henry Wellcome Building, Heath Park, Cardiff, CF14 4XN, UK. jiangw@cf.ac.uk.

ABSTRACT

Background: Hepatocyte growth factor (HGF) is a cytokine that has a profound effect on cancer cells by stimulating migration and invasion and acting as an angiogenic factor. In lung cancer, the factor also plays a pivotal role and is linked to a poor outcome in patients. In particular, HGF is known to work in combination with EGF on lung cancer cells. In the present study, we investigated the effect of a traditional Chinese medicine reported in cancer therapies, namely YangZheng XiaoJi (YZXJ) on lung cancer and on HGF mediated migration and invasion of lung cancer cells.

Methods: Human lung cancer cells, SKMES1 and A549 were used in the study. An extract from the medicine was used. Cell migration was investigated using the EVOS and by ECIS. Cell-matrix adhesion and in vitro invasion were assessed. In vivo growth of lung cancer was tested using an in vivo xenograft tumour model and activation of the HGF receptor in lung tumours by an immunofluorescence method.

Results: Both lung cancer cells increased their migration in response to HGF and responded to YZXJ by reducing their speed of migration. YZXJ markedly reduced the migration and in vitro invasiveness induced by HGF. It worked synergistically with PHA665752 and SU11274, HGF receptor inhibitors on the lung cancer cells both on HGF receptor activation and on cell functions. A combination of HGF and EGF resulted in a greater increase in cell migration, which was similarly inhibited by YZXJ, and in combination with the HGF receptor and EGF receptor inhibitors. In vivo, YZXJ reduced the rate of tumour growth and potentiated the effects of PHA665752 on tumour growth. It was further revealed that YZXJ significantly reduced the degree of phosphorylation of the HGF receptor in lung tumours.

Conclusion: YZXJ has a significant role in reducing the migration, invasion and in vivo tumour growth of lung cancer and acts to inhibit the migratory and invasive effects induced by HGF and indeed by HGF/EGF. This effect is likely attributed to the inhibition of the HGF receptor activation. These results indicate that YZXJ has a therapeutic role in lung cancer and that combined strategy with methods to block HGF and EGF should be considered.

No MeSH data available.


Related in: MedlinePlus