Metabolomics analyses reveal the crucial role of ERK in regulating metabolic pathways associated with the proliferation of human cutaneous T‐cell lymphoma cells treated with Glabridin

• Published in: Cell proliferation Vol. 57; no. 9; pp. e13701 - n/a
• Main Authors: Khan, Abdul Q., Agha, Maha Victor, Ahmad, Fareed, Anver, Rasheeda, Sheikhan, Khalid Sultan A. M., Mateo, Jericha, Alam, Majid, Buddenkotte, Joerg, Uddin, Shahab, Steinhoff, Martin
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.09.2024; John Wiley and Sons Inc
• Subjects: Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Bortezomib; Cancer; Cancer therapies; Cell activation; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chromatography; Deregulation; Disease; Enzymes; Epigenetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Flow cytometry; Humans; Isoflavones - pharmacology; Kinases; Lymphocytes; Lymphoma; Lymphoma, T-Cell, Cutaneous - drug therapy; Lymphoma, T-Cell, Cutaneous - metabolism; Lymphoma, T-Cell, Cutaneous - pathology; Malignancy; MAP kinase; MAP Kinase Signaling System - drug effects; Metabolic Networks and Pathways - drug effects; Metabolic pathways; Metabolic rate; Metabolism; Metabolites; Metabolomics; Necrosis; Original; Pathogenesis; Phenols - pharmacology; Proteins; Reagents; Regulatory proteins; Remission; Signal transduction; Skin cancer; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Skin resistance; T-cell lymphoma; United States > US; California
• ISSN: 0960-7722; 1365-2184; 1365-2184
• DOI: 10.1111/cpr.13701

Cutaneous T‐cell lymphomas (CTC) are a heterogeneous group of T‐cell lymphoproliferative malignancies of the skin with limited treatment options, increased resistance and remission. Metabolic reprogramming is vital in orchestrating the uncontrolled growth and proliferation of cancer cells. Importantly, deregulated signalling plays a significant role in metabolic reprogramming. Considering the crucial role of metabolic reprogramming in cancer‐cell growth and proliferation, target identification and the development of novel and multi‐targeting agents are imperative. The present study explores the underlying mechanisms and metabolic signalling pathways associated with Glabridin mediated anti‐cancer actions in CTCL. Our results show that Glabridin significantly inhibits the growth of CTCL cells through induction of programmed cell death (PCD) such as apoptosis, autophagy and necrosis. Interestingly, results further show that Glabridin induces PCD in CTCL cells by targeting MAPK signalling pathways, particularly the activation of ERK. Further, Glabridin also sensitized CTCL cells to the anti‐cancer drug, bortezomib. Importantly, LC–MS‐based metabolomics analyses further showed that Glabridin targeted multiple metabolites and metabolic pathways intricately involved in cancer cell growth and proliferation in an ERK‐dependent fashion. Overall, our findings revealed that Glabridin induces PCD and attenuates the expression of regulatory proteins and metabolites involved in orchestrating the uncontrolled proliferation of CTCL cells through ERK activation. Therefore, Glabridin possesses important features of an ideal anti‐cancer agent. The present study shows that Glabridin induces programmed cell death, metabolic regulation and spheroid inhibition through ERK activation and sensitizes CTCL cells to bortezomib.