UMMS Affiliation

Department of Surgery; Department of Pathology

Date

5-4-2005

Document Type

Article

Subjects

Alternative Splicing; Base Sequence; Benzo(a)pyrene; Carcinogens; Cell Line, Tumor; Cell Nucleus; Cell Transformation, Neoplastic; Cytochrome P-450 CYP1A1; Epithelium; Estradiol; Female; Humans; Isoenzymes; Mitochondria; Molecular Sequence Data; Ovarian Neoplasms; Ovary; RNA, Messenger; Subcellular Fractions; Transfection

Disciplines

Cancer Biology | Medical Pathology | Surgery

Abstract

Epithelial ovarian cancer derived from the human ovarian surface epithelium (HOSE) is the leading cause of death from gynecologic malignancies among American women. Metabolic activation of endogenous and exogenous chemicals by cytochrome P450 (CYP) class I enzymes has been implicated in its etiology. In this study, we showed overexpression of CYP1A1 mRNA, but not CYP1B1 transcripts, in ovarian cancer cell lines when compared with primary cultures or immortalized HOSE cell lines. Importantly, we identified a novel, enzymatically active, spliced variant of CYP1A1 (CYP1A1v) formed by excision of an 84-bp cryptic intron in exon 2. CYP1A1v is overexpressed in ovarian cancer cell lines and exhibits a unique subcellular distribution restricted to the nucleus and mitochondria, contrary to the endoplasmic reticulum localization of the wild-type enzyme. In concordance, total CYP1A1 activity, as measured by the ethoxyresorufin O-deethylase assay, was detected in mitochondrial, nuclear, and microsomal fractions of ovarian cancer cells but was notably absent in all subcellular fractions of HOSE cells. Immunocytochemistry studies in 30 clinical specimens revealed overexpression of CYP1A1 in various types of ovarian cancers compared with benign epithelia and frequent localization of the enzyme to cancer cell nuclei. Forced expression of CYP1A1wt or CYP1A1v in HOSE cells resulted in nuclear localization of the enzyme and acquisition of anchorage-independent growth, which was further exacerbated following exposure to benzo(a)pyrene or 17beta-estradiol. Collectively, these data provided the first evidence that CYP1A1 overexpression and alternative splicing could contribute to ovarian cancer initiation and progression.

Rights and Permissions

Citation: Cancer Res. 2005 May 1;65(9):3726-34. Link to article on publisher's site

DOI of Published Version

10.1158/0008-5472.CAN-04-3771

Related Resources

Link to article in PubMed

Journal Title

Cancer research

PubMed ID

15867368

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