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

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.

Endosomal system genetics and autism spectrum disorders: A literature review

“…An avenue less studied is the protein-protein interaction network of these central proteins, although some progress has been made in cancer research. One study showed that SLC9A9 expression impacts esophageal cancer cell response to chemotherapy (Chen et al, 2015). It was found that SLC9A9 overexpression was associated with an increase in signaling through RACK1 (Chen et al, 2015).…”

“…One study showed that SLC9A9 expression impacts esophageal cancer cell response to chemotherapy (Chen et al, 2015). It was found that SLC9A9 overexpression was associated with an increase in signaling through RACK1 (Chen et al, 2015). This signaling cascade involves direct interaction and activation of Akt, specifically through the phosphorylation of Ser473 and consequently signaling beta-catenin and Bcl-2 (Chen et al, 2015).…”

“…It was found that SLC9A9 overexpression was associated with an increase in signaling through RACK1 (Chen et al, 2015). This signaling cascade involves direct interaction and activation of Akt, specifically through the phosphorylation of Ser473 and consequently signaling beta-catenin and Bcl-2 (Chen et al, 2015). Functionally, this directly facilitated cell survival and decreased treatment response (Chen et al, 2015).…”

“…This signaling cascade involves direct interaction and activation of Akt, specifically through the phosphorylation of Ser473 and consequently signaling beta-catenin and Bcl-2 (Chen et al, 2015). Functionally, this directly facilitated cell survival and decreased treatment response (Chen et al, 2015). This study emphasized the rich signaling cascades that are downstream of SLC9A9 and the potential affect of loss or gain of function.…”

SLC9A9 Co‐expression modules in autism‐associated brain regions

“…SLC9A9 was reported to regulate the expression levels of growth factor receptors and the transferrin receptor in glioblastoma cells [Kondapalli et al, ]. Additionally, it was associated with increased signaling through Akt/β‐catenin and cell survival signals in esophageal cancer cells [Chen et al, ]. We found that it was co‐regulated with FGFR, MAPK, PI3K , protein translational machinery and localization, and neuronal apoptosis.…”