title: A Role for OCT4 in Tumor Initiation of Drug-Resistant Prostate Cancer Cells.
abstract: Drug resistance remains a clinical challenge in cancer treatment due to poor understanding of underlying mechanisms. We have established several drug-resistant prostate cancer cell lines by long-term culture in medium containing chemotherapeutic drugs. These resistant lines displayed a significant increase in side population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1/Pgp. To uncover potential mechanisms underlying drug resistance, we performed microarray analysis to identify differentially expressed genes in 2 drug-resistant lines. We observed that POU5F1/OCT4, a transcription factor key to regulating pluripotency in embryonic stem cells, was upregulated in drug-resistant lines and accompanied by transcriptional activation of a set of its known target genes. Upregulation of OCT4 in drug-resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmation by Western blot and specific shRNA knockdown. Analysis of the regulatory region of POU5F1/OCT4 revealed a reduction of methylation in drug-resistant cell lines. Furthermore, these drug-resistant cells exhibited a significant increase in tumorigenicity in vivo. Subcutaneous inoculation of as few as 10 drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions, suggesting that these drug-resistant cells may be enriched for tumor-initiating cells. Knocking down OCT4 expression by specific shRNAs attenuated growth of drug-resistant cells. Our data suggest that OCT4 re-expression in cancer cells may play an important role in carcinogenesis and provide one possible mechanism by which cancer cells acquire/maintain a drug-resistant phenotype.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics and The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Linn
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Feng
authors.initials: F
authors.lastname: Sun
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Xie
authors.forename: Hege
authors.initials: H
authors.lastname: Chen
authors.forename: Richeng
authors.initials: R
authors.lastname: Jiang
authors.forename: Hegang
authors.initials: H
authors.lastname: Chen
authors.forename: Saranya
authors.initials: S
authors.lastname: Chumsri
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Burger
authors.forename: Yun
authors.initials: Y
authors.lastname: Qiu