Limits...
The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.

Liu W, Yue F, Zheng M, Merlot A, Bae DH, Huang M, Lane D, Jansson P, Lui GY, Richardson V, Sahni S, Kalinowski D, Kovacevic Z, Richardson DR - Oncotarget (2015)

Bottom Line: Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1.Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation.In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China.

ABSTRACT
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration summarizing the EGFR-c-Src-Rac1 pathway and the inhibitory effect of NDRG1 on cell migration as demonstrated in this investigationNDRG1 expression inhibits c-Src phosphorylation at its activating site (Tyr416). This occurs through NDRG1-induced reduction in EGFR expression, abrogation of EGF-mediated EGFR activation, and thus preventing the EGFR-c-Src interaction. Moreover, NDRG1 is shown to suppress Rac1 activity by modulating the phosphorylation of a c-Src downstream effector, namely p130Cas and its association to CrkII, which acts as a molecular switch to activate Rac1. Additionally, NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, namely c-Abl activation, which inhibited the phosphorylation of CrkII which is required for activation of Rac1 signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4496188&req=5

Figure 10: Schematic illustration summarizing the EGFR-c-Src-Rac1 pathway and the inhibitory effect of NDRG1 on cell migration as demonstrated in this investigationNDRG1 expression inhibits c-Src phosphorylation at its activating site (Tyr416). This occurs through NDRG1-induced reduction in EGFR expression, abrogation of EGF-mediated EGFR activation, and thus preventing the EGFR-c-Src interaction. Moreover, NDRG1 is shown to suppress Rac1 activity by modulating the phosphorylation of a c-Src downstream effector, namely p130Cas and its association to CrkII, which acts as a molecular switch to activate Rac1. Additionally, NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, namely c-Abl activation, which inhibited the phosphorylation of CrkII which is required for activation of Rac1 signaling.

Mentions: Recent studies have demonstrated that NDRG1 acts as a metastasis suppressor with its expression correlating with the inhibition of cancer progression in vivo and cancer cell migration and invasion in vitro [21, 28–31, 56, 67–69]. However, the precise molecular mechanisms underlying these anti-metastatic effects of NDRG1 are not fully understood. Herein, we deciphered a novel mechanism by which NDRG1 mediates its inhibitory functions on cancer cell migration in prostate and colorectal cancer cells. In the current investigation, we demonstrate that NDRG1 expression has a unique role in decreasing c-Src activation by reducing both EGFR expression and activation, as well as its binding to c-Src. Moreover, NDRG1 inhibited Rac1 activation downstream of c-Src through down-regulating p130Cas phosphorylation, which prevents p130Cas-CrkII complex formation, and thus, Rac1 activation (Figure 10). Additionally, NDRG1 also decreased the phosphorylation and activation of c-Abl, resulting in the suppression of CrkII phosphorylation which occurred through a mechanism independent of the inhibition of c-Src (Figure 10). Hence, significantly, this is the first report demonstrating that NDRG1 compromises c-Src activation by modulating EGFR and its interaction with c-Src. Subsequently, this effect attenuates downstream signaling of c-Src, namely by inhibiting the p130Cas-CrkII-Rac1 pathway, leading to inhibition of cancer cell migration.


The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.

Liu W, Yue F, Zheng M, Merlot A, Bae DH, Huang M, Lane D, Jansson P, Lui GY, Richardson V, Sahni S, Kalinowski D, Kovacevic Z, Richardson DR - Oncotarget (2015)

Schematic illustration summarizing the EGFR-c-Src-Rac1 pathway and the inhibitory effect of NDRG1 on cell migration as demonstrated in this investigationNDRG1 expression inhibits c-Src phosphorylation at its activating site (Tyr416). This occurs through NDRG1-induced reduction in EGFR expression, abrogation of EGF-mediated EGFR activation, and thus preventing the EGFR-c-Src interaction. Moreover, NDRG1 is shown to suppress Rac1 activity by modulating the phosphorylation of a c-Src downstream effector, namely p130Cas and its association to CrkII, which acts as a molecular switch to activate Rac1. Additionally, NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, namely c-Abl activation, which inhibited the phosphorylation of CrkII which is required for activation of Rac1 signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496188&req=5

Figure 10: Schematic illustration summarizing the EGFR-c-Src-Rac1 pathway and the inhibitory effect of NDRG1 on cell migration as demonstrated in this investigationNDRG1 expression inhibits c-Src phosphorylation at its activating site (Tyr416). This occurs through NDRG1-induced reduction in EGFR expression, abrogation of EGF-mediated EGFR activation, and thus preventing the EGFR-c-Src interaction. Moreover, NDRG1 is shown to suppress Rac1 activity by modulating the phosphorylation of a c-Src downstream effector, namely p130Cas and its association to CrkII, which acts as a molecular switch to activate Rac1. Additionally, NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, namely c-Abl activation, which inhibited the phosphorylation of CrkII which is required for activation of Rac1 signaling.
Mentions: Recent studies have demonstrated that NDRG1 acts as a metastasis suppressor with its expression correlating with the inhibition of cancer progression in vivo and cancer cell migration and invasion in vitro [21, 28–31, 56, 67–69]. However, the precise molecular mechanisms underlying these anti-metastatic effects of NDRG1 are not fully understood. Herein, we deciphered a novel mechanism by which NDRG1 mediates its inhibitory functions on cancer cell migration in prostate and colorectal cancer cells. In the current investigation, we demonstrate that NDRG1 expression has a unique role in decreasing c-Src activation by reducing both EGFR expression and activation, as well as its binding to c-Src. Moreover, NDRG1 inhibited Rac1 activation downstream of c-Src through down-regulating p130Cas phosphorylation, which prevents p130Cas-CrkII complex formation, and thus, Rac1 activation (Figure 10). Additionally, NDRG1 also decreased the phosphorylation and activation of c-Abl, resulting in the suppression of CrkII phosphorylation which occurred through a mechanism independent of the inhibition of c-Src (Figure 10). Hence, significantly, this is the first report demonstrating that NDRG1 compromises c-Src activation by modulating EGFR and its interaction with c-Src. Subsequently, this effect attenuates downstream signaling of c-Src, namely by inhibiting the p130Cas-CrkII-Rac1 pathway, leading to inhibition of cancer cell migration.

Bottom Line: Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1.Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation.In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China.

ABSTRACT
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.

No MeSH data available.


Related in: MedlinePlus