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Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells.

ABSTRACT: Chemoresistance in gastric cancer is the leading cause of tumor recurrence and poses a substantial therapeutic challenge. The stem cell biomarker CD133 has been implicated in drug resistance of tumor-initiating cells in a number of cancers including gastric cancer. Therefore, we investigated the molecular mechanism of CD133-associated multidrug resistance in gastric cancer cells. Using CD133 overexpressing and knockdown gastric cancer cell lines, we demonstrated that loss of CD133 significantly increased the growth inhibition of chemotherapeutic agents; whereas, overexpression significantly reduced growth inhibition. Furthermore, CD133 knockdown significantly reduced the enzymatic activity of phosphatidylinositol-3 kinase (PI3K) and the expression of P-glycoprotein (P-gp), B-cell lymphoma 2 (BCL2), and phosphorylated-protein kinase B (p-AKT), but elevated the expression of BCL2 associated X (BAX). Conversely, overexpression of CD133 significantly increased PI3K enzymatic activity, expression of P-gp, BCL2, and p-AKT, and decreased BAX expression. The PI3K/AKT inhibitor LY294002 mirrored the effects of loss of CD133; whereas, the PI3K/AKT activator epidermal growth factor reproduced the effects of CD133 overexpression. To identify the interaction between CD133 and PI3K, we used site-directed mutagenesis to mutate individual tyrosine residues of CD133. We found that binding between CD133 and p85, the regulatory subunit of PI3K, was significantly reduced when tyrosine 852 was mutated. In summary, we have demonstrated that CD133 activates the PI3K/AKT signal transduction pathway through direct interaction with PI3K-p85, resulting in multidrug resistance of gastric cancer cells. These results suggest that the interaction between CD133 and PI3K-p85 may offer a novel therapeutic target in multidrug resistant gastric cancer.

SUBMITTER: Song S

PROVIDER: S-EPMC5801368 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells.

Song Shuzheng S Pei Guoqing G Du Yaqiong Y Wu Jugang J Ni Xiaochun X Wang Shoulian S Jiang Bojian B Luo Meng M Yu Jiwei J

American journal of translational research 20180115 1

Chemoresistance in gastric cancer is the leading cause of tumor recurrence and poses a substantial therapeutic challenge. The stem cell biomarker CD133 has been implicated in drug resistance of tumor-initiating cells in a number of cancers including gastric cancer. Therefore, we investigated the molecular mechanism of CD133-associated multidrug resistance in gastric cancer cells. Using CD133 overexpressing and knockdown gastric cancer cell lines, we demonstrated that loss of CD133 significantly ...[more]

PMID: 29423015

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Project description:Background5-fluorouracil (5-FU)-based chemotherapy regimen has been widely used for the treatment of gastric cancer, but meanwhile the development of chemotherapeutic resistance remains a major clinical challenge. Tumor microenvironment (TME) frequently correlates with the development of chemoresistance in human cancer. As a major component of TME, the role of tumor-associated macrophages (TAMs) in the chemoresistance of gastric cancer has not been fully elucidated.MethodsImmunohistochemistry (IHC) was applied to detect the density of TAMs in clinical samples of 103 patients with gastric cancer who had undergone 5-FU-based neoadjuvant chemotherapy. 5-FU-resistant gastric cell lines MKN45-R and HGC27-R were established, macrophages were then separately co-cultured with MKN45-R, HGC27-R cells and their parental cells. The effect of gastric cancer cells on the polarization of macrophages, the biological function of M2-polaried macrophages and the mechanism for promoting 5-FU-resistance were investigated. Then the correlation between the expression of CXC motif chemokine ligand 5 (CXCL5) and the infiltration of hemoglobin scavenger receptor (CD163) positive and mannose receptor (CD206) positive macrophages was analyzed, the prognostic value of CXCL5 expression in clinical samples was further explored.ResultsThe high infiltration of macrophages marked by CD68 in gastric cancer samples was significantly associated with the resistance of gastric cancer to chemotherapy. Gastric cancer cells could modulate macrophages to M2-like polarization through indirect co-culture, and chemoresistant cells were more efficient in inducing macrophages polarization to M2 phenotype. Co-culturing M2-polarized macrophages in turn enhanced 5-FU-resistance of gastric cancer cells, and it was further verified that CXCL5 derived from M2-polarized macrophages promoted chemoresistance through activing the PI3K/AKT/mTOR pathway. Besides, high level of CXCL5 could recruit monocytes to form more M2-polarized macrophages. Clinically, high expression of CXCL5 in gastric cancer samples was associated with the high infiltration of CD163 positive macrophages and CD206 positive macrophages, and patients with high expression of CXCL5 presented lower overall survival (OS) rates than those with low expression of CXCL5.ConclusionInteraction between TAMs and gastric cancer cells promoted chemoresistance in gastric cancer via CXCL5/PI3K/AKT/mTOR pathway. Thus, targeting TAMs and blocking the cell-cell crosstalk between TAMs and gastric cancer cells may represent prospective therapeutic strategies for patients with gastric cancer.

Project description:Recently, a small population of cancer stem cells in adult and pediatric brain tumors has been identified. Some evidence has suggested that CD133 is a marker for a subset of leukemia and glioblastoma cancer stem cells. Especially, CD133 positive cells isolated from human glioblastoma may initiate tumors and represent novel targets for therapeutics. The gene expression and the drug resistance property of CD133 positive cancer stem cells, however, are still unknown.In this study, by FACS analysis we determined the percentage of CD133 positive cells in three primary cultured cell lines established from glioblastoma patients 10.2%, 69.7% and 27.5%, respectively. We also determined the average mRNA levels of markers associated with neural precursors. For example, CD90, CD44, CXCR4, Nestin, Msi1 and MELK mRNA on CD133 positive cells increased to 15.6, 5.7, 337.8, 21.4, 84 and 1351 times, respectively, compared to autologous CD133 negative cells derived from cell line No. 66. Additionally, CD133 positive cells express higher levels of BCRP1 and MGMT mRNA, as well as higher mRNA levels of genes that inhibit apoptosis. Furthermore, CD133 positive cells were significantly resistant to chemotherapeutic agents including temozolomide, carboplatin, paclitaxel (Taxol) and etoposide (VP16) compared to autologous CD133 negative cells. Finally, CD133 expression was significantly higher in recurrent GBM tissue obtained from five patients as compared to their respective newly diagnosed tumors.Our study for the first time provided evidence that CD133 positive cancer stem cells display strong capability on tumor's resistance to chemotherapy. This resistance is probably contributed by the CD133 positive cell with higher expression of on BCRP1 and MGMT, as well as the anti-apoptosis protein and inhibitors of apoptosis protein families. Future treatment should target this small population of CD133 positive cancer stem cells in tumors to improve the survival of brain tumor patients.

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Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells.

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Interaction between CD133 and PI3K-p85 promotes chemoresistance in gastric cancer cells.

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