K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr virus (EBV)--associated nasopharyngeal carcinoma cells.
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 BDNF-induced 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 EBV-associated human cancer cells, namely NPC cells. This proof-of-concept study demonstrated that K252a, a Trk inhibitor, can potentially be used as an anoikis-sensitizing agent in NPC.
Ng
Yuen-Keng
YK
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR, China.
Wong
Elaine Yue Ling
EY
Lau
Cecilia Pik Yuk
CP
Chan
Jessica Pui Lan
JP
Wong
Sze Chuen Cesar
SC
Chan
Andrew Sai-Kit
AS
Kwan
Maggie Pui Chun
MP
Tsao
Sai-Wah
SW
Tsang
Chi-Man
CM
Lai
Paul Bo San
PB
Chan
Anthony Tak Cheung
AT
Lui
Vivian Wai Yan
VW
D023102:Anoikis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D002277:Carcinoma; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020813:Receptor, trkB / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D026121:Indole Alkaloids; D047428:Protein Kinase Inhibitors; C049985:staurosporine aglycone; D020813:Receptor, trkB