한빛사논문
- 조회556
Nikita Gupta a,1, Chakrabhavi Dhananjaya Mohan b,1, Muthu K. Shanmugam a,1, Young Yun Jung c, Arunachalam Chinnathambi d, Sulaiman Ali Alharbi d, Milad Ashrafizadeh e, Manas Mahale f, Andreas Bender g, Alan Prem Kumar a, Thomas Choudary Putti h, Kanchugarakoppal S. Rangappa i, Xianbin Zhang e, Kwang Seok Ahn c, Gautam Sethi a
aDepartment of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
bDepartment of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore, 570006, India [Present address: FEST Division CSIR-Indian Institute of Toxicology Research Vishvigyan Bhawan 31, Mahatma Gandhi Marg Lucknow - 226 001 Uttar Pradesh, India]
cDepartment of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea
dDepartment of Botany and Microbiology, College of Science, King Saud University, PO Box -2455, Riyadh, 11451, Saudi Arabia
eDepartment of General Surgery and Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, Guangdong, 518055, China
fDepartment of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India
gCentre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
hDepartment of Pathology, National University of Singapore, National University Hospital, Kent Ridge Road, Singapore, 119074, Singapore
iInstitution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, 570006, India
1NG, CDM, and MKS contributed equally to this work and therefore equal first authors.
Corresponding authors: Kwang Seok Ahn, Gautam Sethi
Abstract
Environmental factors such as exposure to ionizing radiations, certain environmental pollutants, and toxic chemicals are considered as risk factors in the development of breast cancer. Triple-negative breast cancer (TNBC) is a molecular variant of breast cancer that lacks therapeutic targets such as progesterone receptor, estrogen receptor, and human epidermal growth factor receptor-2 which makes the targeted therapy ineffective in TNBC patients. Therefore, identification of new therapeutic targets for the treatment of TNBC and the discovery of new therapeutic agents is the need of the hour. In this study, CXCR4 was found to be highly expressed in majority of breast cancer tissues and metastatic lymph nodes derived from TNBC patients. CXCR4 expression is positively correlated with breast cancer metastasis and poor prognosis of TNBC patients suggesting that suppression of CXCR4 expression could be a good strategy in the treatment of TNBC patients. Therefore, the effect of Z-guggulsterone (ZGA) on the expression of CXCR4 in TNBC cells was examined. ZGA downregulated protein and mRNA expression of CXCR4 in TNBC cells and proteasome inhibition or lysosomal stabilization had no effect on the ZGA-induced CXCR4 reduction. CXCR4 is under the transcriptional control of NF-κB, whereas ZGA was found to downregulate transcriptional activity of NF-κB. Functionally, ZGA downmodulated the CXCL12-driven migration/invasion in TNBC cells. Additionally, the effect of ZGA on growth of tumor was investigated in the orthotopic TNBC mice model. ZGA presented good inhibition of tumor growth and liver/lung metastasis in this model. Western blotting and immunohistochemical analysis indicated a reduction of CXCR4, NF-κB, and Ki67 in tumor tissues. Computational analysis suggested PXR agonism and FXR antagonism as targets of ZGA. In conclusion, CXCR4 was found to be overexpressed in majority of patient-derived TNBC tissues and ZGA abrogated the growth of TNBC tumors by partly targeting the CXCL12/CXCR4 signaling axis.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-07-06)
- 국내(교신)+국외 연구진
- 의약학 > 약학
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