Carcinogenesis Advance Access published online on October 20, 2009
Carcinogenesis, doi:10.1093/carcin/bgp253
Cucurbitacin I Elicits Anoikis-sensitization, Inhibits Cellular Invasion and In Vivo Tumor Formation Ability of Nasopharyngeal Carcinoma Cells
1 Cancer Signaling Laboratory
2 Cancer Drug Testing Unit
6 State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR
3 Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR
4 Department of Anatomy, University of Hong Kong, Hong Kong SAR
Corresponding Author: Anthony Tak-Cheung Chan, Corresponding address: Department of Clinical Oncology, State Key Lab in Oncology in South China, Sir YK Pao Center for Cancer, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, Telephone number : 852-2632-2099, Fax number : 852-2648-8842, Email : anthony{at}clo.cuhk.edu.hk
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 animal 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 genes (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.
Key Words: Cucurbitacin I • anoikis-sensitization • invasion • tumorigenicity • Nasopharyngeal cancer (NPC)
* denotes equal contribution to this work
Received April 8, 2009; revised October 9, 2009; accepted October 11, 2009.