Merlin is encoded by the NF2 gene and, as a tumor suppressor, stalls cell proliferation by contact-dependent growth inhibition. Prior work from our laboratory has established that Merlin levels are significantly decreased in breast tumor tissues representing advanced grade. Moreover, Merlin expression is completely lost in cases representing metastatic breast cancer. Therefore, we mimicked Merlin deficiency by stably knocking down NF2 in non-metastatic breast cancer cells. Recognizing the role of metabolic reprogramming in tumor progression, we undertook untargeted metabolomics analysis - this effort identified low levels of reduced glutathione (GSH) in Merlin-deficient cells. Given the role of GSH as the most abundant antioxidant cofactor, we explored if a major reactive oxygen species (ROS) clearance mechanism is compromised in Merlin-deficient breast cancer cells. Indeed, accumulated levels of ROS were detected in Merlin-deficient cells, suggesting that Merlin deficiency causes redox imbalance. Quenching of elevated ROS levels attenuated migration and invasion capabilities indicating a role of ROS in intensifying malignant behaviors upon Merlin deficiency. Furthermore, dysregulated STAT3 activity upregulated the expression of NADPH oxidase (NOX) enzymes in Merlin-deficient breast cancer cells compared to their control counterparts. These findings were also recapitulated in non-tumorigenic Nf2 −/- mouse embryonic fibroblasts further supporting the key role of Merlin in these phenotypes. In conclusion, ROS accumulation and increased malignancy in Merlin-deficient cells may be the result of a dysregulated cellular redox management system.
Citation Format: Mateus Mota, Brandon Metge, Lalita Shevde-Samant. Merlin deficiency induces redox imbalance in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3572.