Premium
Direct and Natural Killer cell‐mediated anti‐tumor effects of low‐dose Bortezomib in Hepatocellular Carcinoma
Author(s) -
Krusch Matthias,
Armeanu Sorin,
Baltz Katrin M.,
Lauer Ulrich M.,
Steinle Alexander,
Bitzer Michael,
Salih Helmut R.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1077.4
Subject(s) - bortezomib , cancer research , cytotoxicity , nkg2d , proteasome inhibitor , cell , chemistry , natural killer cell , hepatocellular carcinoma , lymphokine activated killer cell , proteasome , immunology , biology , t cell , interleukin 21 , immune system , in vitro , multiple myeloma , biochemistry
Hepatocellular carcinoma (HCC) displays a particular resistance to conventional cytostatic agents. Therefore, alternative treatment strategies focus on novel substances exhibiting anti‐neoplastic and/or immunomodulatory activity enhancing e.g. NK cell reactivity. However, the tumor‐associated ligands engaging activating NK cell receptors are largely unknown. Exceptions are the NKG2D ligands (NKG2DL) of the MIC and ULBP families. We here studied the consequences of proteasome inhibition with regard to direct and NK cell‐mediated effects against primary human hepatocytes (PHH) from different donors and hepatoma cells. Bortezomib treatment inhibited hepatoma cell growth with IC 50 values between 2.4 and 7.7 nM. These low doses increased MICA/B mRNA levels and protein expression in hepatoma cells, which stimulated cytotoxicity and IFN‐γ production of cocultured NK cells. Importantly, while IFN‐γ production of NK cells was concentration‐dependently reduced, low‐dose Bortezomib neither induced NKG2DL expression or cell death in PHH nor altered NK cell cytotoxicity. Thus, low‐dose Bortezomib mediates a specific dual anti‐tumor effect in HCC by inhibiting proliferation and by priming hepatoma cells for NK cell anti‐tumor reactivity. Our data suggest the clinical evaluation of Bortezomib treatment in HCC, especially in combination with immunotherapeutic approaches like adoptive NK cell transfer.