Cucurbitacin I elicits anoikis sensitization, inhibits cellular invasion and in vivo tumor formation ability of nasopharyngeal carcinoma cells.
Nasopharyngeal carcinoma (NPC) is an Asian-prevalent head and neck cancer with high invasiveness. Although several important risk factors for NPC development have been identified, there is currently no preventive strategy for NPC, even in endemic regions. Signal transducer and activator of transcription 3 (STAT3) has been implicated in NPC carcinogenesis, which may serve as a potential target for cancer prevention. Here, we examined the chemopreventive potential of Cucurbitacin I, a natural-occurring selective inhibitor of JAK/STAT3, in NPC models. We hypothesized that Cucurbitacin I would prevent NPC invasion and tumor formation. Our data demonstrated that brief exposure of NPC cells to Cucurbitacin I was sufficient to significantly reduce the in vitro clonogenicity and in vivo tumorigenicity of NPC cells. The chemopreventive potential of Cucurbitacin I was further demonstrated by pre-dosing of the animals with Cucurbitacin I prior to tumor inoculation, which was found to be able to suppress tumor growth up to 7 days post-inoculation. The anti-proliferation activity of Cucurbitacin I was accompanied by downregulation of phospho-STAT3 and STAT3 target gene expression (e.g. cyclin D1 and Mcl-1). Cucurbitacin I also reduced the invasiveness of invasive NPC cell lines with elevated STAT3 activation. Furthermore, our data demonstrated for the first time that Cucurbitacin I harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against human cancer. Taken together, our results suggested that Cucurbitacin I may be a potent chemopreventive agent for NPC with anti-invasion and anoikis-sensitizing activities.
Lui
Vivian W Y
VW
Cancer Signaling Laboratory, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
Yau
Daisy M S
DM
Wong
Elaine Y L
EY
Ng
Yuen-Keng
YK
Lau
Cecilia P-K
CP
Ho
Yeung
Y
Chan
Jessica P L
JP
Hong
Bo
B
Ho
Kakiu
K
Cheung
Crystal S
CS
Tsang
Chi-Man
CM
Tsao
Sai-Wah
SW
Chan
Anthony T C
AT
D000818:Animals; D023102:Anoikis; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007797:Laminin / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014315:Triterpenes / Q000378:metabolism* / Q000494:pharmacology
D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014315:Triterpenes; C059485:matrigel; D003094:Collagen; C038106:cucurbitacin I