Clofazimine inhibits small-cell lung cancer progression by modulating the kynurenine/aryl hydrocarbon receptor axis.

Autor: Sharma G; Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-68198, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-68198, USA., Abdullah KM; Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-68198, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-68198, USA., Qais FA; Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh, UP 202002, India., Khan P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA., Cox JL; Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha NE-68198, USA., Sarwar T; Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia., Nasser MW; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha NE-68198, USA., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE-68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha NE-68198, USA., Siddiqui JA; Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson MS-68198, USA; Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson MS-68198, USA. Electronic address: jsiddiqui@umc.edu.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Oct 26, pp. 136921. Date of Electronic Publication: 2024 Oct 26.
DOI: 10.1016/j.ijbiomac.2024.136921
Abstrakt: Small cell lung cancer (SCLC) is one of the highly metastatic malignancies that contributes to ~15 % of all lung cancers. Most SCLC patients (50-60 %) develop osteolytic bone metastases, significantly affecting their quality of life. Among several factors, environmental pollutant 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) and kynurenine (Kyn), an endogenous ligand derived from tryptophan (Trp) metabolism, activate the aryl hydrocarbon receptor (AhR) and are responsible for SCLC progression and metastasis. Further, elevated AhR expression in bone cells intensifies bone resorption, making the Kyn/AhR axis a potential target for the bone metastatic propensity of SCLC. We first assessed the expression profile of AhR in human SCLC cell lines and found a significantly increased expression compared to normal lung cells. Additionally, we also evaluated the clinical significance of AhR expression in the patient samples of SCLC along with the relevance of the same in the Rb1 fl/fl ; Trp53 fl/fl ; Myc LSL/LSL (RPM) mouse model using immunohistochemistry and found the higher AhR expression in the patient samples and RPM mouse tumor tissues. Using computational simulations, we found that clofazimine (CLF) binds at the activator (Kyn) binding site by forming a stable complex with AhR. The CLF binding with AhR was favored by Van der Waals and hydrophobic forces, and the proteins retained their secondary structure. Furthermore, we found that Kyn treatment potentiates the migration and clonogenic ability of SCLC cell lines by activating Erk/Akt oncogenic signaling. Blocking AhR with CLF reduces AhR expression, inhibits Kyn-mediated proliferation of SCLC cells, and induces apoptosis and cell cycle arrest in the G2/M phase; further, our examination indicates that Kyn treatment also promotes osteoblast-mediated osteoclast differentiation through RANKL. The treatment with CLF impedes RANKL expression and osteoclastogenesis, suggesting that CLF has the potential for developing SCLC therapies that have efficacies against bone metastasis.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no potential conflicts of interest.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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