TY - JOUR
T1 - K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma cells
AU - Ng, Yuen Keng
AU - Wong, Elaine Yue Ling
AU - Lau, Cecilia Pik Yuk
AU - Chan, Jessica Pui Lan
AU - Wong, Sze Chuen Cesar
AU - Chan, Andrew Sai Kit
AU - Kwan, Maggie Pui Chun
AU - Tsao, Sai Wah
AU - Tsang, Chi Man
AU - Lai, Paul Bo San
AU - Chan, Anthony Tak Cheung
AU - Lui, Vivian Wai Yan
N1 - Funding Information:
Acknowledgement This study was supported by Direct Grant for Research, The Chinese University of Hong Kong (2008.1.101 to YKN). Result of this study was presented in part in the poster session at the American Association of Cancer Research (AACR) annual meeting, Colorado, USA, 2009.
PY - 2012/2
Y1 - 2012/2
N2 - Recent studies revealed an unexpected role of the neurotrophin receptor pathway, BDNF/TrkB signaling, in cancer metastasis and anoikis (i.e. detachment-induced cell death). Survival of cancer cells in detached state (known as anoikis-resistance) is known to be pre-requisite for metastasis. Nasopharyngeal carcinoma (NPC), an endemic head and neck cancer in Southeast Asia, is highly invasive, metastatic, and etiologically associated with Epstein-Barr virus (EBV, an oncovirus) infection. Mechanistic studies on the invasive/metastatic nature of NPC can facilitate the development of anti-metastatic therapy in NPC. Thus far, the role of BDNF/TrkB signaling in virus-associated human cancer is unclear. Here, using multiple cell line models of NPC with EBV-association (HONE-1-EBV, HK1-LMP1 and C666-1), we investigated the potential involvement of BDNF/TrkB signaling in cellular migration and anoikis-resistant characteristics of NPC. We found that all three EBV-associated NPC cell lines tested were intrinsically anoikis-resistant (i.e. survived in detached state) and expressed both BDNF and TrkB. BDNF stimulation induced cellular migration, but not proliferation of these cells. Further, we examined if pharmacologic targeting of anoikis-resistance of NPC cells can be achievable by a proof-of-concept Trk inhibitor, K252a, in these EBV-associated NPC models. Our results demonstrated that K252a, was able to attenuate BDNFinduced migration and proliferation of NPC cells. More importantly, we demonstrated for the first time that K252a harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against EBVassociated human cancer cells, namely NPC cells. This proofof- concept study demonstrated that K252a, a Trk inhibitor, can potentially be used as an anoikis-sensitizing agent in NPC.
AB - Recent studies revealed an unexpected role of the neurotrophin receptor pathway, BDNF/TrkB signaling, in cancer metastasis and anoikis (i.e. detachment-induced cell death). Survival of cancer cells in detached state (known as anoikis-resistance) is known to be pre-requisite for metastasis. Nasopharyngeal carcinoma (NPC), an endemic head and neck cancer in Southeast Asia, is highly invasive, metastatic, and etiologically associated with Epstein-Barr virus (EBV, an oncovirus) infection. Mechanistic studies on the invasive/metastatic nature of NPC can facilitate the development of anti-metastatic therapy in NPC. Thus far, the role of BDNF/TrkB signaling in virus-associated human cancer is unclear. Here, using multiple cell line models of NPC with EBV-association (HONE-1-EBV, HK1-LMP1 and C666-1), we investigated the potential involvement of BDNF/TrkB signaling in cellular migration and anoikis-resistant characteristics of NPC. We found that all three EBV-associated NPC cell lines tested were intrinsically anoikis-resistant (i.e. survived in detached state) and expressed both BDNF and TrkB. BDNF stimulation induced cellular migration, but not proliferation of these cells. Further, we examined if pharmacologic targeting of anoikis-resistance of NPC cells can be achievable by a proof-of-concept Trk inhibitor, K252a, in these EBV-associated NPC models. Our results demonstrated that K252a, was able to attenuate BDNFinduced migration and proliferation of NPC cells. More importantly, we demonstrated for the first time that K252a harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against EBVassociated human cancer cells, namely NPC cells. This proofof- concept study demonstrated that K252a, a Trk inhibitor, can potentially be used as an anoikis-sensitizing agent in NPC.
KW - Anoikis-sensitization
KW - BDNF
KW - K252a
KW - Nasopharyngeal carcinoma (NPC)
KW - TrkB tyrosine kinase
UR - http://www.scopus.com/inward/record.url?scp=84856529862&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856529862&partnerID=8YFLogxK
U2 - 10.1007/s10637-010-9513-4
DO - 10.1007/s10637-010-9513-4
M3 - Article
C2 - 20694504
AN - SCOPUS:84856529862
SN - 0167-6997
VL - 30
SP - 48
EP - 58
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 1
ER -