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Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.

Zhao Y, Zhang J, Tian Y, Xue C, Hu Z, Zhang L - Drug Des Devel Ther (2015)

Bottom Line: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo.Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

ABSTRACT

Purpose: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.

Experimental design: Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed.

Results: Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 μmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus 5.3±0.9, P=0.06). HGF was widely expressed in both primary and metastatic lesions while Met expression of metastatic lesions was higher than that of primary lesions (primary lesions: 24.7%; liver metastases: 40%; lung metastases: 29%; lymph node metastases: 29%, P<0.05), and overall survival of NPC patients with higher expression of Met was shorter (P=0.13).

Conclusion: Our results demonstrated that HGF/Met signaling promoted NPC growth, further resulting in metastasis and poor prognosis. Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin. Our study implied that HGF/Met signaling was the potential therapeutic target in NPC, and blockage of the signaling could prevent growth and metastasis of NPC and derive clinical benefit.

No MeSH data available.


Related in: MedlinePlus

PF-2341066 downregulated activation of Met signaling pathway in HNE-1.Notes: (A) Expression and activation of Met in NPC cell lines. Expression of Met in NPC was examined by Western blot. Total Met and, phosphorylated Met was tested after treatment with 50 ng/mL HGF for 24 hours, and GAPDH is shown as control. Met expression can be found in all NPC cell lines and the normal epithelial cell line NP69, but phosphorylated Met was only detected in NPC cells. (B) Western blot of cell lines. NPC cells were serum-starved for 12 hours followed by treatment with increasing concentrations of PF-2341066 and stimulated with 50 ng/mL HGF for 24 hours. The expression of phosphorylated Met, AKT, and ERK were reversed compared with the control group. The expression of Snail and vimentin were also inhibited, which was proved to be related with epithelial mesenchymal transition.Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.
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f3-dddt-9-4897: PF-2341066 downregulated activation of Met signaling pathway in HNE-1.Notes: (A) Expression and activation of Met in NPC cell lines. Expression of Met in NPC was examined by Western blot. Total Met and, phosphorylated Met was tested after treatment with 50 ng/mL HGF for 24 hours, and GAPDH is shown as control. Met expression can be found in all NPC cell lines and the normal epithelial cell line NP69, but phosphorylated Met was only detected in NPC cells. (B) Western blot of cell lines. NPC cells were serum-starved for 12 hours followed by treatment with increasing concentrations of PF-2341066 and stimulated with 50 ng/mL HGF for 24 hours. The expression of phosphorylated Met, AKT, and ERK were reversed compared with the control group. The expression of Snail and vimentin were also inhibited, which was proved to be related with epithelial mesenchymal transition.Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.

Mentions: We examined the total Met and phosphorylated Met in NPC cell lines and the normal epithelial cell line NP69 with or without drug treatment. We found that total Met protein expressed in all cells but phosphorylated Met was only detected in cancer cells (Figure 3A). As shown in Figure 3B, PF-2341066 inhibited Met phosphorylation, and two key downstream effector molecules of HGF/Met, AKT and ERK, were induced by HGF in a concentration-dependent fashion. The expression of Snail and vimentin were also inhibited, which was proved to be related with epithelial mesenchymal transition (EMT).


Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.

Zhao Y, Zhang J, Tian Y, Xue C, Hu Z, Zhang L - Drug Des Devel Ther (2015)

PF-2341066 downregulated activation of Met signaling pathway in HNE-1.Notes: (A) Expression and activation of Met in NPC cell lines. Expression of Met in NPC was examined by Western blot. Total Met and, phosphorylated Met was tested after treatment with 50 ng/mL HGF for 24 hours, and GAPDH is shown as control. Met expression can be found in all NPC cell lines and the normal epithelial cell line NP69, but phosphorylated Met was only detected in NPC cells. (B) Western blot of cell lines. NPC cells were serum-starved for 12 hours followed by treatment with increasing concentrations of PF-2341066 and stimulated with 50 ng/mL HGF for 24 hours. The expression of phosphorylated Met, AKT, and ERK were reversed compared with the control group. The expression of Snail and vimentin were also inhibited, which was proved to be related with epithelial mesenchymal transition.Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555972&req=5

f3-dddt-9-4897: PF-2341066 downregulated activation of Met signaling pathway in HNE-1.Notes: (A) Expression and activation of Met in NPC cell lines. Expression of Met in NPC was examined by Western blot. Total Met and, phosphorylated Met was tested after treatment with 50 ng/mL HGF for 24 hours, and GAPDH is shown as control. Met expression can be found in all NPC cell lines and the normal epithelial cell line NP69, but phosphorylated Met was only detected in NPC cells. (B) Western blot of cell lines. NPC cells were serum-starved for 12 hours followed by treatment with increasing concentrations of PF-2341066 and stimulated with 50 ng/mL HGF for 24 hours. The expression of phosphorylated Met, AKT, and ERK were reversed compared with the control group. The expression of Snail and vimentin were also inhibited, which was proved to be related with epithelial mesenchymal transition.Abbreviations: GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPC, nasopharyngeal carcinoma.
Mentions: We examined the total Met and phosphorylated Met in NPC cell lines and the normal epithelial cell line NP69 with or without drug treatment. We found that total Met protein expressed in all cells but phosphorylated Met was only detected in cancer cells (Figure 3A). As shown in Figure 3B, PF-2341066 inhibited Met phosphorylation, and two key downstream effector molecules of HGF/Met, AKT and ERK, were induced by HGF in a concentration-dependent fashion. The expression of Snail and vimentin were also inhibited, which was proved to be related with epithelial mesenchymal transition (EMT).

Bottom Line: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo.Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

ABSTRACT

Purpose: We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.

Experimental design: Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed.

Results: Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 μmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus 5.3±0.9, P=0.06). HGF was widely expressed in both primary and metastatic lesions while Met expression of metastatic lesions was higher than that of primary lesions (primary lesions: 24.7%; liver metastases: 40%; lung metastases: 29%; lymph node metastases: 29%, P<0.05), and overall survival of NPC patients with higher expression of Met was shorter (P=0.13).

Conclusion: Our results demonstrated that HGF/Met signaling promoted NPC growth, further resulting in metastasis and poor prognosis. Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin. Our study implied that HGF/Met signaling was the potential therapeutic target in NPC, and blockage of the signaling could prevent growth and metastasis of NPC and derive clinical benefit.

No MeSH data available.


Related in: MedlinePlus