K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma cells

Yuen Keng Ng, Elaine Yue Ling Wong, Cecilia Pik Yuk Lau, Jessica Pui Lan Chan, Sze Chuen Cesar Wong, Andrew Sai Kit Chan, Maggie Pui Chun Kwan, Sai Wah Tsao, Chi Man Tsang, Paul Bo San Lai, Anthony Tak Cheung Chan, Vivian Wai Yan Lui

Research output: Journal article publicationJournal articleAcademic researchpeer-review

14 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)48-58
Number of pages11
JournalInvestigational New Drugs
Volume30
Issue number1
DOIs
Publication statusPublished - 1 Feb 2012
Externally publishedYes

Keywords

  • Anoikis-sensitization
  • BDNF
  • K252a
  • Nasopharyngeal carcinoma (NPC)
  • TrkB tyrosine kinase

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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