Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression

Abstract

Tumor cells often produce high levels of reactive oxygen species (ROS) and display an increased ROS scavenging system. However, the molecular mechanism that balances antioxidative and oxidative stress in cancer cells is unclear. Here, we determined that oncogenic multiple copies in T-cell malignancy 1 (MCT-1) activity promotes the generation of intracellular ROS and mitochondrial superoxide. Overexpression of MCT-1 suppresses p53 accumulation but elevates the manganese-dependent superoxide dismutase (MnSOD) level via the YY1-EGFR signaling cascade, which protects cells against oxidative damage. Conversely, restricting ROS generation and/or targeting YY1 in lung cancer cells effectively inhibits the EGFR-MnSOD signaling pathway and cell invasiveness induced by MCT-1. Significantly, MCT-1 overexpression in lung cancer cells promotes tumor progression, necrosis and angiogenesis, and increases the number of tumor-promoting M2 macrophages and cancer-associated fibroblasts in the microenvironment. Clinical evidence further confirms that high expression of MCT-1 is associated with an increase in YY1, EGFR and MnSOD expression, accompanied by tumor recurrence, poor overall survival and EGFR mutation status in patients with lung cancers. Together, these data indicate that the MCT-1 oncogenic pathway is implicated in oxidative metabolism and lung carcinogenesis.

Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression

“…Furthermore, K-Ras(G12D) [45], B-Raf(V619E) and Myc oncogenes induce NRF2 antioxidant program, by which enhance ROS detoxification and tumorigenesis. Besides, the activation of MCT-1 oncogene capably induces YY1-EGFR signaling axis that promotes MnSOD expression [35], mitochondrial ROS generation, lung cancer cell invasion and tumor progression. Here, we identify that Oligo-Fucoidan combined with cisplatin treatment induces ROS signaling in colorectal cancer cells which can be suppressed by antioxidants (NAC, MitoQ and DPI) (Supplementary Figure S7B), demonstrating that Oligo-Fucoidan and cisplatin together induce the oxidative signaling axis of YY1/EGFR/MnSOD (Supplementary Figure S7).…”

“…Glutathione peroxidase (GPX) diminishes ROS buildup and reduces oxidative damage [34]. Under the oncogenic stress [35], YY1 induction and EGFR activation are stimulated that lead to MnSOD expression and ROS generation. Similarly, cisplatin and Oligo-Fucoidan collectively amplified the ROS signaling pathway in HCT116 (p53 −/− and p53 +/+ ) cells (Supplementary Figure S7A), which showed increase of YY1, EGFR, EGFR phosphorylation (p-EGFR) (Tyr1068), MnSOD and γ-H2AX but decrease of GPX.…”

The Yin and Yang of YY1 in tumor growth and suppression

“…MCT‐1 overexpression in A549 lung cancer cells promoted tumor progression in nude mice, reduced levels of p53 and induced levels of YY1, pEGFR and MnSOD within the tumors. High MCT‐1 expression is associated with increased YY1, EGFR and MnSOD expression and poor overall survival in patients with lung cancers …”

Redox control of cancer cell destruction

“… Tumor-associated macrophages MCF-10A and A549 cell lines, mouse xenograft model in vitro/in vivo Oncogenic MCT-1 (multiple copies in T-cell malignancy 1) activity promotes oxidant generation. Overexpression of MCT-1 elevates MnSOD level via the YY1-EGFR signaling cascade, which protects cells against oxidative damage [184] . Oxidants inhibit MΦ-mediated cancer cell killing Human peripheral blood mononuclear cells (PBMC) CAFs isolated from pancreatic tumor, Human pancreatic cancer cell line Panc1 and Miapaca2 in vitro Pancreatic cancer-associated fibroblasts (CAFs) induce a tumor-promoting TAM phenotype in monocytes Secreted M-CSF from CAFs led to enhanced H 2 O 2 production and M2 polarization in monocytes [185] .…”

“… Tumor-associated macrophages MCF-10A and A549 cell lines, mouse xenograft model in vitro/in vivo Oncogenic MCT-1 (multiple copies in T-cell malignancy 1) activity promotes oxidant generation. Overexpression of MCT-1 elevates MnSOD level via the YY1-EGFR signaling cascade, which protects cells against oxidative damage [184] . Peritoneal cavity and spleen-derived macrophages Mice inoculated with Ehrlich ascites tumor (EAT) cells in vivo CA (caffeic acid) inhibited tumor growth and ascites volume in mice bearing Ehrlich ascites tumor (EAT).…”