Down-regulation of human topoisomerase IIα correlates with... : Anti-Cancer Drugs (original) (raw)

PRECLINICAL REPORTS

Down-regulation of human topoisomerase IIα correlates with altered expression of transcriptional regulators NF-YA and Sp1

Allen, Kirsty A.a; Williams, Amram O.a; Isaacs, Richard J.b; Stowell, Kathryn M.a

aInstitute of Molecular BioSciences, Massey University, Palmerston North, New Zealand

bMedical Oncology Unit, MidCentral Health, Palmerston North, New Zealand

Sponsorship: This work was supported by a grant from the Cancer Society of New Zealand.

Correspondence to K. M. Stowell, Institute of Molecular BioSciences, Massey University, Private Bag 11-222, Palmerston North, New Zealand.

Tel: +64 06 350 5515 extn 7517; fax: +64 06 350 5688;

e-mail: [email protected]

Received 15 December 2003 Accepted 6 January 2004

Abstract

Topoisomerase IIα (Topo IIα) is an essential nuclear enzyme with a role in the maintenance of DNA topology. Topo IIα is a target for several anticancer drugs and the levels of activity of this enzyme have been implicated in the development of drug resistance. Our objective was to identify regulatory transcription factors involved in drug-induced down-regulation of Topo IIα. A breast cancer cell line was subjected to a pulsed exposure of doxorubicin and resistant clones propagated. Whole-cell extracts were studied by immunoblotting and RT-PCR for drug-induced changes in the amounts Topo IIα, Sp1, Sp3, NF-Y and MDR1. Topo IIα levels were reduced in six out of eight cell lines. Of these, three showed concomitant changes in the expression of Sp1 and NF-YA. Thus, we provide the first evidence for roles of Sp1 and NF-Y in bringing about the drug-induced down-regulation of Topo IIα gene expression.