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Silibinin induces metabolic crisis in triple‐negative breast cancer cells by modulating EGFR‐MYC‐TXNIP axis: potential therapeutic implications
Author(s) -
Iqbal Mohammad Askandar,
Chattopadhyay Shilpi,
Siddiqui Farid Ahmad,
Ur Rehman Asad,
Siddiqui Shumaila,
Prakasam Gopinath,
Khan Asifa,
Sultana Sarwat,
Bamezai Rameshwar NK
Publication year - 2021
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15353
Subject(s) - triple negative breast cancer , silibinin , txnip , cancer research , warburg effect , anaerobic glycolysis , glycolysis , cancer cell , biology , medicine , cancer , breast cancer , metabolism , oxidative stress , thioredoxin
Triple‐negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment modalities and poor prognosis. Metabolic reprogramming in cancer is considered a hallmark of therapeutic relevance. Here, we report disruption of metabolic reprogramming in TNBC cells by silibinin via modulation of EGFR‐MYC‐TXNIP signaling. Metabolic assays combined with LC‐MS‐based metabolomics revealed inhibition of glycolysis and other key biosynthetic pathways by silibinin, to induce metabolic catastrophe in TNBC cells. Silibinin‐induced metabolic suppression resulted in decreased cell biomass, proliferation, and stem cell properties. Mechanistically, we identify EGFR‐MYC‐TXNIP as an important regulator of TNBC metabolism and mediator of inhibitory effects of silibinin. Highlighting the clinical relevance of our observations, the analysis of METABRIC dataset revealed deregulation of EGFR‐MYC‐TXNIP axis in TNBC and association of EGFR high ‐MYC high ‐TXNIP low signature with aggressive glycolytic metabolism and poor disease‐specific and metastasis‐free survival. Importantly, combination treatment of silibinin or 2‐deoxyglucose (glycolysis inhibitor) with paclitaxel synergistically inhibited proliferation of TNBC cells. Together, our results highlight the importance of EGFR‐MYC‐TXNIP axis in regulating TNBC metabolism, demonstrate the anti‐TNBC activity of silibinin, and argue in favor of targeting metabolic vulnerabilities of TNBC, at least in combination with mainstay chemotherapeutic drugs, to effectively treat TNBC patients.