Neurokinin-1 receptor as a therapeutic target in hepatoblastoma

Garnier, Agnès (2016): Neurokinin-1 receptor as a therapeutic target in hepatoblastoma. Dissertation, LMU München: Faculty of Medicine

Abstract

The neurokinin-1 receptor (NK1R) has recently been described as being pivotal in the development of cancer. NK1R antagonists, such as the clinical drug aprepitant, are therefore under current investigation as future innovative anticancer agents. However, little is known about the NK1R complex as a potential target in hepatoblastoma and colon cancer cells. Thus, we aimed at investigating the impact of NK1R inhibition with aprepitant on cell growth, apoptosis, downstream mechanims and cancer stem cells in three human hepatoblastoma cell lines HepT1, HepG2 and HuH6 and the human colon cancer cell lines LiM6 and DLD1. Finally, mRNA from 47 children with hepatoblastoma were analysed regarding both full length and truncated forms of NK1R. NK1R is highly expressed in human hepatoblastoma cell lines predominantly in its truncated version. Following NK1R blockage by aprepitant, a significant growth inhibition of hepatoblastoma cells and colon cancer cells as well as induction of apoptosis was detected, which was associated with the downregulation of two critical signaling pathways, namely Wnt and PI3K/AKT/mTOR. Further, treatment of colon cancer or hepatoblastoma cells grown under cancer stem cell conditions reduced sphere formation in number and size as well as expression of the stemness markers SOX2, NANOG, and OCT4. From a clinical perspective, both forms of NK1R were generally overexpressed in hepatoblastoma cases, without any correlation with clinicopathological parameters indicating that aprepitant might be used in a wide variety of hepatoblastoma. Taken together, these findings give important insight into the molecular mechanisms of the NK1R as a critical component in tumorigenesis and can help in the development of future anticancer therapies for Wnt-activated cancers such as hepatoblastoma and colon cancer.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 29. June 2016
• 1. Referee: Kappler, Roland
• Signature of the printed copy: 0700/UMD 17193