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MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells.

ABSTRACT: BACKGROUND:Immunotherapy and its mechanisms are being studied in a wide variety of cancers. Programmed cell death ligand 1 (PDL1) is associated with immune evasion in numerous tumor types. Here, we aimed to assess the relationship between metastasis associated in colon cancer-1 (MACC1) and PDL1 and examine their effects on gastric cancer (GC) tumor immunity. METHODS:The expression of MACC1, c-Met, and PDL1 in human GC tissues was first assessed using quantitative RT-PCR (qRT-PCR) and immunohistochemistry. We then focused on the relationships among MACC1, c-Met, and PDL1 using RT-PCR and western blotting after cell transfection and inhibitor treatment in vitro and on the identification of their roles in immune killing in vitro and in vivo. RESULTS:We found that expression of MACC1, c-Met, and PDL1 was upregulated in human GC tissues, and there was a positive correlation between the expression levels. In addition, we found that ectopic expression of MACC1 (silencing and overexpression by transfection) resulted in corresponding changes in c-Met and PDL1 expression levels, and c-Met/AKT/mTOR pathway inhibitors (SU11274, MK2206, and rapamycin) blocked the regulation of PDL1 expression by MACC1. Furthermore, silencing of MACC1 led to an increase in antitumor and immune killing in vitro and in vivo, and overexpression of MACC1 resulted in a decrease in tumor immunity in vitro and in vivo. CONCLUSIONS:From these data, we infer that MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in GC cells and suggest that MACC1 may be a therapeutic target for GC immunotherapy.

SUBMITTER: Tong G

PROVIDER: S-EPMC6853821 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells.

Tong Gangling G Cheng Boran B Li Jingzhang J Wu Xuan X Nong Qiaohong Q He Lirui L Li Xi X Li Laiqing L Wang Shubin S

Cancer medicine 20190926 16

<h4>Background</h4>Immunotherapy and its mechanisms are being studied in a wide variety of cancers. Programmed cell death ligand 1 (PDL1) is associated with immune evasion in numerous tumor types. Here, we aimed to assess the relationship between metastasis associated in colon cancer-1 (MACC1) and PDL1 and examine their effects on gastric cancer (GC) tumor immunity.<h4>Methods</h4>The expression of MACC1, c-Met, and PDL1 in human GC tissues was first assessed using quantitative RT-PCR (qRT-PCR) ...[more]

PMID: 31557409

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Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy. DLBCL cell lines were tested for Rapamycin sensitivity and classified as "sensitive" or "resistant." Genome-wide analysis of all cell lines were performed using the Affymetrix HuGene ST 1.0 Array Platform. Genes with differential expression between sensitive and resistant cell lines were analyzed using Statistical Analysis of Microarrays (SAM) software, and a signature of genes determnined. This signature was found to accurately predict sensitivity or resistance of other DLBCL cell lines, and to identify the protein kinase Akt as central to resistance.

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Dataset Information

MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells.

Publications

MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells.

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