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ERBB3 is required for metastasis formation of melanoma cells.

Tiwary S, Preziosi M, Rothberg PG, Zeitouni N, Corson N, Xu L - Oncogenesis (2014)

Bottom Line: Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro.These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs.In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

ABSTRACT
Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic melanoma are urgently needed. Here we report that ERBB3, a member of the epidermal growth factor receptor family, is required for the formation of lung metastasis from both the BI-sensitive melanoma cell line, MA-2, and the BI-resistant melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of melanoma cells in lung but is required for their further development into overt metastases, indicating that ERBB3 might be essential for the survival of melanoma cells after they reach the lung. Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

No MeSH data available.


Related in: MedlinePlus

NRG1 induces ERBB3-dependent AKT phosphorylation in MA-2 and 451Lu-R cells in vitro. (a, b) MA-2 (a) and 451Lu-R (b) cells were stimulated with NRG1 for 0, 15, 30, 60 or 120 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT. γ-tubulin was used as a loading control. (c) qRT–PCR analyses of Nrg1 mRNA in the mouse lungs and in MA-2 or 451Lu-R cells. Three independent experiments were performed and graphed. (d) A panel of melanoma cell lines were stimulated with NRG1 for 0, 15 or 30 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT (top panel). γ-tubulin was used as a loading control. Band intensities were quantified by the ImageJ software (bottom panel).
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fig5: NRG1 induces ERBB3-dependent AKT phosphorylation in MA-2 and 451Lu-R cells in vitro. (a, b) MA-2 (a) and 451Lu-R (b) cells were stimulated with NRG1 for 0, 15, 30, 60 or 120 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT. γ-tubulin was used as a loading control. (c) qRT–PCR analyses of Nrg1 mRNA in the mouse lungs and in MA-2 or 451Lu-R cells. Three independent experiments were performed and graphed. (d) A panel of melanoma cell lines were stimulated with NRG1 for 0, 15 or 30 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT (top panel). γ-tubulin was used as a loading control. Band intensities were quantified by the ImageJ software (bottom panel).

Mentions: As mentioned earlier, ERBB3 is thought to predominantly signal through the PI3K/AKT pathway to regulate cancer cell survival.16, 17, 18 A high-affinity ligand for ERBB3 is neuregulin, NRG1.30 It activates ERBB3 to induce AKT phosphorylation and has been shown to promote melanoma growth.31 We predicted that ERBB3 promotes melanoma metastasis formation via the NRG1-ERBB3-AKT survival pathway. To test this, serum-starved MA-2 cells expressing control shRNA or ERBB3 shRNA were stimulated with 500 ng/ml NRG1 for 15, 30 or 60 min. Robust induction of phospho-ERBB3 and phospho-AKT was observed in the control cells but not in the ERBB3-knockdown cells (Figure 5a). Similar impairment of ERBB3 and AKT phosphorylation was observed in 451Lu-BR cells expressing ERBB3 shRNAs (Figure 5b). These results demonstrate that NRG1 induces ERBB3-dependent AKT activation in MA-2 and 451Lu-R cells in vitro.


ERBB3 is required for metastasis formation of melanoma cells.

Tiwary S, Preziosi M, Rothberg PG, Zeitouni N, Corson N, Xu L - Oncogenesis (2014)

NRG1 induces ERBB3-dependent AKT phosphorylation in MA-2 and 451Lu-R cells in vitro. (a, b) MA-2 (a) and 451Lu-R (b) cells were stimulated with NRG1 for 0, 15, 30, 60 or 120 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT. γ-tubulin was used as a loading control. (c) qRT–PCR analyses of Nrg1 mRNA in the mouse lungs and in MA-2 or 451Lu-R cells. Three independent experiments were performed and graphed. (d) A panel of melanoma cell lines were stimulated with NRG1 for 0, 15 or 30 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT (top panel). γ-tubulin was used as a loading control. Band intensities were quantified by the ImageJ software (bottom panel).
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fig5: NRG1 induces ERBB3-dependent AKT phosphorylation in MA-2 and 451Lu-R cells in vitro. (a, b) MA-2 (a) and 451Lu-R (b) cells were stimulated with NRG1 for 0, 15, 30, 60 or 120 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT. γ-tubulin was used as a loading control. (c) qRT–PCR analyses of Nrg1 mRNA in the mouse lungs and in MA-2 or 451Lu-R cells. Three independent experiments were performed and graphed. (d) A panel of melanoma cell lines were stimulated with NRG1 for 0, 15 or 30 min. Cells were lysed and probed for phospho-ERBB3, total ERBB3, phospho-AKT or total AKT (top panel). γ-tubulin was used as a loading control. Band intensities were quantified by the ImageJ software (bottom panel).
Mentions: As mentioned earlier, ERBB3 is thought to predominantly signal through the PI3K/AKT pathway to regulate cancer cell survival.16, 17, 18 A high-affinity ligand for ERBB3 is neuregulin, NRG1.30 It activates ERBB3 to induce AKT phosphorylation and has been shown to promote melanoma growth.31 We predicted that ERBB3 promotes melanoma metastasis formation via the NRG1-ERBB3-AKT survival pathway. To test this, serum-starved MA-2 cells expressing control shRNA or ERBB3 shRNA were stimulated with 500 ng/ml NRG1 for 15, 30 or 60 min. Robust induction of phospho-ERBB3 and phospho-AKT was observed in the control cells but not in the ERBB3-knockdown cells (Figure 5a). Similar impairment of ERBB3 and AKT phosphorylation was observed in 451Lu-BR cells expressing ERBB3 shRNAs (Figure 5b). These results demonstrate that NRG1 induces ERBB3-dependent AKT activation in MA-2 and 451Lu-R cells in vitro.

Bottom Line: Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro.These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs.In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

ABSTRACT
Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic melanoma are urgently needed. Here we report that ERBB3, a member of the epidermal growth factor receptor family, is required for the formation of lung metastasis from both the BI-sensitive melanoma cell line, MA-2, and the BI-resistant melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of melanoma cells in lung but is required for their further development into overt metastases, indicating that ERBB3 might be essential for the survival of melanoma cells after they reach the lung. Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

No MeSH data available.


Related in: MedlinePlus