Cordyceps militaris Exerts Anticancer Effect on Non–Small Cell Lung Cancer by Inhibiting Hedgehog Signaling via Suppression of TCTN3

Abstract

This study aimed to investigate the effect of Cordyceps militaris extract on the proliferation and apoptosis of non–small cell lung cancer (NSCLC) cells and determine the underlying mechanisms. We performed a CCK-8 assay to detect cell proliferation, detection of morphological changes through transmission electron microscopy (TEM), annexin V–FITC/PI double staining to analyze apoptosis, and immunoblotting to measure the protein expression of apoptosis and hedgehog signaling–related proteins, with C militaris treated NSCLC cells. In this study, we first found that C militaris reduced the viability and induced morphological disruption in NSCLC cells. The gene expression profiles indicated a reprogramming pattern of genes and transcription factors associated with the action of TCTN3 on NSCLC cells. We also confirmed that the C militaris–induced inhibition of TCTN3 expression affected the hedgehog signaling pathway. Immunoblotting indicated that C militaris–mediated TCTN3 downregulation induced apoptosis in NSCLC cells, involved in the serial activation of caspases. Moreover, we demonstrated that the C militaris negatively modulated GLI1 transcriptional activity by suppressing SMO/PTCH1 signaling, which affects the intrinsic apoptotic pathway. When hedgehog binds to the PTCH1, SMO dissociates from PTCH1 inhibition at cilia. As a result, the active GLI1 translocates to the nucleus. C militaris clearly suppressed GLI1 nuclear translocation, leading to Bcl-2 and Bcl-xL down-regulation. These results suggested that C militaris induced NSCLC cell apoptosis, possibly through the downregulation of SMO/PTCH1 signaling and GLI1 activation via inhibition of TCTN3. Taken together, our findings provide new insights into the treatment of NSCLC using C militaris.

Cordyceps militaris as a Bio Functional Food Source: Pharmacological Potential, Anti-Inflammatory Actions and Related Molecular Mechanisms

“…Another mechanism of the apoptosis of lung carcinoma by C. militaris extracts is related to downregulation of TCTN3 expression, which affected the hedgehog signaling cascade and contributed to the serial activation of caspases. Additionally, the extract negatively modulated GLI1 transcriptional activity by inhibiting SMO/PTCH1 molecules, subsequently regulating the intrinsic apoptotic signaling cascade [92]. All these findings support the possible use of C. militaris extracts as anticancer agents in future studies.…”

Cordyceps militaris: An Overview of Its Chemical Constituents in Relation to Biological Activity

“…Reduction in TCTN3 expression correlated with the suppression of different signaling pathways such as: Smoothened (SMO), Patched1 (PTCH1) and gliomaassociated (GLI1) pathways. The aforementioned processes correlate with decreased Bcl-2, BclxL, and increased Bak, cleaved caspase-3 and caspase-9 levels [92].…”

How Should the Worldwide Knowledge of Traditional Cancer Healing Be Integrated with Herbs and Mushrooms into Modern Molecular Pharmacology?

“…Another study reported that the Cm extract overcame cisplatin resistance in NSCLC cell lines when proteomic profile analysis revealed H-Ras down-regulation [ 429 ]. Other authors have demonstrated that its extract down-regulated hedgehog signaling in NSCLCs via TCTN3 inhibition and GLI1 nuclear translocation suppression [ 430 ].…”