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Biomolecules. 2019 Sep 30;9(10). pii: E550. doi: 10.3390/biom9100550.

Brusatol, a Nrf2 Inhibitor Targets STAT3 Signaling Cascade in Head and Neck Squamous Cell Carcinoma.

Author information

1
College of Korean Medicine, Kyung Hee University, #47, Kyungheedae-gil, Dongdaemoon-gu, Seoul 130-701, Korea. 88mirue@gmail.com.
2
Adichunchanagiri Institute for Molecular Medicine, BG Nagara-571448, Nagamangala Taluk, Mandya District 571448, India. shobithrangappa@gmail.com.
3
Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India. cd.mohan@yahoo.com.
4
Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India. salundibasappa@gmail.com.
5
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore. phcgs@nus.edu.sg.
6
Faculty of Medicine, The Chinese University of Hong Kong, Rm 101, 1/F Li Wai Chun Building, CUHK, Shatin, N.T. 999077, Hong Kong. linzx@cuhk.edu.hk.
7
Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India. rangappaks@yahoo.com.
8
College of Korean Medicine, Kyung Hee University, #47, Kyungheedae-gil, Dongdaemoon-gu, Seoul 130-701, Korea. ksahn@khu.ac.kr.

Abstract

STAT3 is a latent transcription factor that plays a vital role in the transmission of extracellular signal from receptors to the nucleus. It has been regarded as a master transcription factor due to its role in the regulation of a broad spectrum of genes, which can contribute to oncogenesis. Persistent activation of STAT3 and deregulation of its signaling has been observed in various human cancers including head and neck squamous cell carcinoma (HNSCC). In the present work, we identified brusatol (BT) as a potential blocker of STAT3 signaling pathway in diverse HNSCC cells. The data from the cell-based experiments suggested that BT-induced cytotoxicity and abrogated the activation of STAT3 and that of upstream kinases such as JAK1, JAK2, and Src. It reduced the levels of nuclear STAT3 and its DNA binding ability. BT treatment increased annexin-V-positive cells, promoted procaspase-3 and PARP cleavage, and downregulated the mRNA and protein expression of diverse proteins (Bcl-2, Bcl-xl, survivin) in HNSCC cells. Taken together, brusatol can function as a promising inhibitor targeting STAT3 signaling pathway in HNSCC.

KEYWORDS:

HNSCC; STAT3 inhibitor; apoptosis; brusatol

PMID:
31575007
DOI:
10.3390/biom9100550
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