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NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression.

Chen J, Yang H, Wen J, Luo K, Liu Q, Huang Y, Zheng Y, Tan Z, Huang Q, Fu J - Oncotarget (2015)

Bottom Line: Our results showed that NHE9 prevented CRT-induced apoptosis.Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling.Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

ABSTRACT
Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT)-resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling. Moreover, upregulated Bcl-2 protein was also observed in cells exhibiting NHE9-induced CRT resistance. A higher NHE9 level was associated with a poor response to CRT and less decrease in T and N stage in ESCC patients. Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression. Taken together, our findings demonstrate that NHE9 can be an effective predictor of CRT response and may be useful in the development of targeted therapies for CRT-resistant ESCC.

No MeSH data available.


Related in: MedlinePlus

NHE9 inhibited apoptosis by activating Src/Akt/β-catenin and upregulating Bcl-2The binding affinity of NHE9 for RACK1 changed after chemotherapy or radiotherapy A–B. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were upregulated in NHE9-overexpressing cells when compared with the corresponding control cells C. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were downregulated in NHE9 knockdown cells when compared with the controls D.
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Figure 5: NHE9 inhibited apoptosis by activating Src/Akt/β-catenin and upregulating Bcl-2The binding affinity of NHE9 for RACK1 changed after chemotherapy or radiotherapy A–B. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were upregulated in NHE9-overexpressing cells when compared with the corresponding control cells C. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were downregulated in NHE9 knockdown cells when compared with the controls D.

Mentions: Interestingly, we found that the interaction between NHE9 and RACK1 was altered after the cells were treated with cisplatin, vinorelbine or X-rays. The immunoprecipitation results showed that the binding of NHE9 to RACK1 was relatively weaker after chemotherapy or radiotherapy, and a similar result was observed after X-ray treatment (Figure 5A and 5B). Therefore, CRT may negatively affect the binding between NHE9 and RACK1. Additionally, NHE9 may affect cell signaling activation by interacting with RACK1.


NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression.

Chen J, Yang H, Wen J, Luo K, Liu Q, Huang Y, Zheng Y, Tan Z, Huang Q, Fu J - Oncotarget (2015)

NHE9 inhibited apoptosis by activating Src/Akt/β-catenin and upregulating Bcl-2The binding affinity of NHE9 for RACK1 changed after chemotherapy or radiotherapy A–B. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were upregulated in NHE9-overexpressing cells when compared with the corresponding control cells C. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were downregulated in NHE9 knockdown cells when compared with the controls D.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494947&req=5

Figure 5: NHE9 inhibited apoptosis by activating Src/Akt/β-catenin and upregulating Bcl-2The binding affinity of NHE9 for RACK1 changed after chemotherapy or radiotherapy A–B. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were upregulated in NHE9-overexpressing cells when compared with the corresponding control cells C. Phosphorylated Akt (Ser473), phosphorylated Src (Tyr416), GSK3β, Bcl-2, and β-catenin were downregulated in NHE9 knockdown cells when compared with the controls D.
Mentions: Interestingly, we found that the interaction between NHE9 and RACK1 was altered after the cells were treated with cisplatin, vinorelbine or X-rays. The immunoprecipitation results showed that the binding of NHE9 to RACK1 was relatively weaker after chemotherapy or radiotherapy, and a similar result was observed after X-ray treatment (Figure 5A and 5B). Therefore, CRT may negatively affect the binding between NHE9 and RACK1. Additionally, NHE9 may affect cell signaling activation by interacting with RACK1.

Bottom Line: Our results showed that NHE9 prevented CRT-induced apoptosis.Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling.Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

ABSTRACT
Recently, we found that NHE9 mRNA was upregulated in chemoradiotherapy (CRT)-resistant esophageal squamous cell carcinoma (ESCC); however, the underlying mechanisms were unclear. Here, we aimed to clarify the functional contribution of NHE9 to CRT resistance, understand the molecular basis of NHE9-dependent resistance in ESCC, and identify potential therapeutic targets. Our results showed that NHE9 prevented CRT-induced apoptosis. Importantly, we found that RACK1 is a novel binding partner of NHE9 and that NHE9-dependent induction of CRT resistance requires the activation of RACK1-associated Src/Akt/β-catenin signaling. Moreover, upregulated Bcl-2 protein was also observed in cells exhibiting NHE9-induced CRT resistance. A higher NHE9 level was associated with a poor response to CRT and less decrease in T and N stage in ESCC patients. Furthermore, combining either Dasatinib or ABT-737 with CRT significantly reduced tumor volume, and the response to CRT was restored when these inhibitors were used together with CRT in a xenograft nude mouse model with NHE9 overexpression. Taken together, our findings demonstrate that NHE9 can be an effective predictor of CRT response and may be useful in the development of targeted therapies for CRT-resistant ESCC.

No MeSH data available.


Related in: MedlinePlus