The AKT1/NF-kappaB/Notch1/PTEN axis has an important role in chemoresistance of gastric cancer cells

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.

JMJD3 and NF-κB-dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing

“…S7a) 32 . The recruitment of JMJD3 and NF-κB p65 to the upstream region of Notch1 gene was investigated in HaCaT keratinocytes after scratching by a ChIP assay.…”

Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

“…The sections were developed using a 3,3 0 -diaminobenzidine tetrahydrochloride (DAB) substrate kit (ThermoScien-tific, MA) at room temperature for 1-5 min and then counterstained with hematoxylin. The intensity of the immunostaining was categorized as follows: no brown particle staining (0), light brown particle (1), moderate brown particle (2), and dark brown particle (3). The extent of immunostaining was quantified by counting the percentage of positive cells and classified into four groups: 0, less than 25% positive cells; 1, 25-50% positive cells; 2, 51-75% positive cells; and 3, more than 75% positive cells.…”

“…Numerous studies indicate that the development and progression of glioma arises via miss-regulation of many related genes such as p53, p21, Akt, Gli1, and PTEN [1][2][3][4][5][6]. However, the regulatory mechanisms remain poorly understood.…”

Expression of Notch-1 and its clinical significance in different histological subtypes of human lung adenocarcinoma

“…Increasing evidences have shown that Notch-1 is involved in the regulation of tumor cell growth, proliferation, apoptosis, metastasis and chemo- or radioresistance. Notch-1 was either reported as an oncogene [7] in some solid tumors, or reported as a tumor suppressor in other tumors [8]. The two different viewpoints were usually resulted from different types of tumors or different stages of tumors.…”