Establishment and some characteristics of epoxomicin (a proteasome inhibitor) resistant variants of the human squamous cell carcinoma cell line, A431.

Abstract:

:A431 resistant variants to epoxomicin (EXM) were established, showing 4.0-6.7 times more resistance to EXM than parental A431P. Both variants demonstrated increased expression of the beta-subunit molecules of 26S proteasome with approximately 2.5 times increased activity. In variant cells, cyclin B and P34cdc2 were over-expressed, whereas P21WAF1 was expressed at a similar level to A431P. Because of the proteasome inhibitor acting as a G2/M blocker, results are to the advantage of resistant cells proliferating in the presence of an inhibitor under a severe environment. Variant cells showed increased expression of epidermal growth factor receptor (EGFR) and decreased expression of mRNA, but also slight accumulation of protein of c-Cbl, which is a negative regulator of EGFR possessing ubiquitin ligase activity to desensitize EGF signaling. UbcH7, acting intimately with c-Cbl, was decreased in level compared to A431P. These phenomena can be regarded as one of the causes of prevention of c-Cbl-mediated down-regulation of EGFR in variant cells, enabling them to live. The anti-apoptotic Bcl-2 mainly consisted of a phosphorylated form with resistance to proteasomal degradation, suggesting that Bcl-2 phosphorylation occurred independently of its apoptotic function. Variant cells showed resistance not only to EXM, but to the 5 proteasome inhibitors, while demonstrating collateral sensitivity to doxorubicin.

journal_name

Int J Oncol

authors

Ohkawa K,Asakura T,Aoki K,Shibata S,Minami J,Fujiwara C,Sai T,Marushima H,Kuzuu H

keywords:

subject

Has Abstract

pub_date

2004-02-01 00:00:00

pages

425-33

issue

2

eissn

1019-6439

issn

1791-2423

journal_volume

24

pub_type

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