title: Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety.
abstract: Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples of oral leukoplakia. With gene microarray and immunostaining, we found 4-nitroquinoline 1-oxide (4NQO) in drink activated the Nrf2 pathway and produced oxidative damage in mouse tongue. Meanwhile whole exome sequencing of mouse tongue identified mutations consistent with 4NQO's mutagenic profile. Using cultured human oral keratinocytes and 4NQO-treated mouse tongue, we found that SFN pre-treatment activated the NRF2 pathway and inhibited oxidative damage both in vitro and in vivo. On the contrary, a structural analogue of SFN without the isothiocyanate moiety did not have such effects. In a long-term chemoprevention study using wild-type and Nrf2-/- mice, we showed that topical application of SFN activated the NRF2 pathway, inhibited oxidative damage, and prevented 4NQO-induced oral carcinogenesis in an Nrf2-dependent manner. Our data clearly demonstrate that SFN has chemopreventive effects on oxidative stress-associated oral carcinogenesis, and such effects depend on Nrf2 and the isothiocyanate moiety.
authors.affiliation: Department of Oral Medicine, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China.
authors.forename: Aixian
authors.initials: A
authors.lastname: Lan
authors.affiliation: Department of Oral Medicine, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Oral Medicine, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cancer Research Program, JLC-BBRI, North Carolina Central University, Durham, NC 27707, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Department of Oral Medicine, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Engineering, School of Pharmaceutical & Life Sciences, Changzhou University, Jiangsu 213164, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Cancer Research Program, JLC-BBRI, North Carolina Central University, Durham, NC 27707, USA.
authors.forename: Olesya
authors.initials: O
authors.lastname: Palko
authors.affiliation: Cancer Research Program, JLC-BBRI, North Carolina Central University, Durham, NC 27707, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Cancer Research Program, JLC-BBRI, North Carolina Central University, Durham, NC 27707, USA.
authors.forename: Mayanga
authors.initials: M
authors.lastname: Kapita
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Prigge
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Schmidt
authors.affiliation: Department of Pharmaceutical Engineering, School of Pharmaceutical & Life Sciences, Changzhou University, Jiangsu 213164, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Oral Medicine, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, Beijing 100050, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Cancer Research Program, JLC-BBRI, North Carolina Central University, Durham, NC 27707, USA.
authors.forename: Xiaoxin Luke
authors.initials: XL
authors.lastname: Chen
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects*; D002273:Carcinogens / Q000633:toxicity; D018890:Chemoprevention / Q000379:methods*; D006801:Humans; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009062:Mouth Neoplasms; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D013454:Sulfoxides
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; D015112:4-Nitroquinoline-1-oxide; C016766:sulforaphane
keywords: 4NQO; NRF2; chemoprevention; oral cancer; sulforaphane