Abstract
The inherent resistance of tumors to DNA damage often limits the efficacy of chemotherapy. The aim of this work is to explore the potential mechanism for development of chemoresistance in gastric cancer. Our data revealed that AKT1 mRNA and protein expression were induced by doxorubicin (a chemotherapeutic agent); the doxorubicin-induced AKT1 expression and activation increased the binding of NF-kappaB on Notch1 DNA promoter and then promoted the Notch1 transcription and expression; enhanced expression of Notch1 further upregulated PTEN expression through CBF-1 binding to PTEN DNA promoter; and inhibition of AKT1 expression and activity sensitized the gastric cancer cell to doxorubicin treatment in cultured gastric cancer cell lines and xenograft nude mice gastric cancer model. Furthermore, our data demonstrated that both Notch1 and PTEN were absent or minimally expressed in gastric cancer tissue but abundant in paired normal gastric mucosa, and the expression of Notch1 correlated with that of PTEN. Together, these novel results suggested that a novel AKT1/NF-kappaB/Notch1/PTEN axis has an important role in the development of chemoresistance in gastric cancer. Notch1 has an anti-cancer role in gastric cancer.
Highlights
Double-strand breaks, has gained broad application for chemotherapy of solid cancer, including gastric cancer.[2,3] like other chemotherapeutic agents, the efficacy of doxorubicin is severely limited because of chemoresistance
We demonstrated that AKT1 mRNA and protein expression were induced by doxorubicin; reactive oxygen species (ROS)/JAK2/STAT3 were the upstream regulators of AKT1 expression; doxorubicin-induced AKT1 expression and activation led to upregulation of Notch[1] expression through increasing NFkB DNA binding activity, this increased Notch[1] expression further promoted PTEN expression through CBF-1 binding to PTEN DNA promoter
Because of the in-parallel upregulation induced by doxorubicin, it was reasonable to ask if there existed a functional linkage among AKT1, Notch[1], and PTEN
Summary
Double-strand breaks, has gained broad application for chemotherapy of solid cancer, including gastric cancer.[2,3] like other chemotherapeutic agents, the efficacy of doxorubicin is severely limited because of chemoresistance. AKT ( named protein kinase B) represents a subfamily of the serine/threonine kinase.[8] Our previous work has described that constitutive and inducible PI3K/AKT activities involve in chemoresistance of gastric cancer cells through a number of targets, including NF-kappaB (NFkB), forkhead transcription factors, caspase-3, and -9; downregulation of PI3K/AKT activities through overexpression of PTEN gene sensitizes gastric cancer cells to chemotherapeutic drugs.[9]. PTEN gene expression is found to be induced by etoposide treatment[12] and UV irradiation.[13] It is reported that PTEN expression can be regulated by Notch-1 signaling through binding CBF-1 to PTEN promoter.[14,15,16]
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