Inhibition of BTK activity in head and neck squamous cell carcinoma (HNSCC) prevents tumor progression and induces cell cycle arrest as well as apoptosis

Introduction:

Recently, two novel BTK isoforms of 80 and 65 kDa have been described to be expressed in solid carcinoma entities. BTK expression seemed to be linked with tumor growth and protection from apoptosis resulting in a poor prognosis of these cancer patients.

Therefore, we aimed to investigate whether these newly identified BTK isoforms are also expressed in HNSCC and to further elucidate the molecular and cellular consequences of BTK expression for HNSCC tumorigenesis.

Material and Methods:

HNSCC-derived cell lines as well as tumor samples were analyzed for BTK-p65 and -p80 expression. The consequences of pharmacological and genetic inhibition of BTK activity for proliferation, cell cycle progression, transmigration, apoptosis and vascularization was analyzed in vitro and in vivo. BTK-mediated oncogenic signal transduction was analyzed at the molecular level.

Results:

BTK-p65 and -p80 isoforms are expressed in HNSCC cell lines as well as in primary HNSCC samples. Pharmacological or genetic targeting of BTK activity leads to inhibition of cell proliferation and transmigration in vitro. These effects were associated with cell cycle arrest and induction of apoptosis. Moreover, in in vivo xenograft experiments, chemically and genetically abrogation of BTK activity impaired tumor growth accompanied with decreased tumor vascularization. Mechanistic analyses revealed an involvement of oncogenic BTK activity in NF-κB-dependent signal transduction.

Conclusion:

Together, our data characterize BTK-p65 as well as BTK-p80 as novel HNSCC-associated oncogenes representing crucial players in the maintenance of HNSCC. Thus, targeting BTK-activity appears to be a promising therapeutic option for patients suffering from BTK-expressing HNSCC.

Publikationsverlauf

Publikationsdatum:
23. April 2019 (online)