Oncotarget

Research Papers:

Bortezomib-resistance is associated with increased levels of proteasome subunits and apoptosis-avoidance

Yi-Xin Wu _, Jia-Hua Yang and Hirotomo Saitsu

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Oncotarget. 2016; 7:77622-77634. https://doi.org/10.18632/oncotarget.12731

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Abstract

Yi-Xin Wu1, Jia-Hua Yang2, Hirotomo Saitsu1

1Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

2Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Correspondence to:

Yi-Xin Wu, email: [email protected]

Keywords: bortezomib resistant, proteasome inhibitor, hepatocellular carcinoma cell, BCL2, apoptosis

Received: August 02, 2016    Accepted: October 04, 2016    Published: October 18, 2016

ABSTRACT

Bortezomib (BTZ), a proteasome inhibitor, is the first proteasome inhibitor to be used in clinical practice. Here we investigated the mechanisms underlying acquired bortezomib resistance in hepatocellular carcinoma (HCC) cells. Using stepwise selection, we established two acquired bortezomib-resistant HCC cell lines, a bortezomib-resistant HepG2 cell line (HepG2/BTZ) and bortezomib-resistant HuH7 cell line (HuH7/BTZ). The 50% inhibitory concentration values of HepG2/BTZ and HuH7/BTZ were respectively 15- and 39-fold higher than those of parental cell lines. Sequence analysis of the bortezomib-binding pocket in the β5-subunit showed no mutation. However, bortezomib-resistant HCC cells had increased expression of β1 and β5 proteasome subunits. These alterations of proteasome expression were accompanied by a weak degree of proteasome inhibition in bortezomib-resistant cells than that in wild-type cells after bortezomib exposure. Furthermore, bortezomib-resistant HCC cells acquired resistance to apoptosis. Bortezomib up-regulated pro-apoptotic proteins of the Bcl-2 protein family, Bax and Noxa in wild-type HCC cells. However, in bortezomib-resistant HCC cells, resistance to apoptosis was accompanied by loss of the ability to stabilize and accumulate these proteins. Thus, increased expression and increased activity of proteasomes constitute an adaptive and auto regulatory feedback mechanism to allow cells to survive exposure bortezomib.


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