Abstract
Sustained adrenergic stimulation by norepinephrine (NE) contributes to ovarian carcinoma metastasis and impairment of chemotherapy response. Although the effect of sustained NE stimulation in cancer progression is well established, less is known about its role in cancer initiation. To determine the extent to which stress hormones influence ovarian cancer initiation, we conducted a long-term (> 3 months; > 40 population doublings) experiment in which normal immortalized fallopian tube secretory (iFTSEC283) and ovarian surface epithelial (iOSE11) cell lines and their isogenic pairs containing a p53 mutation (iFTSEC283p53R175H; iOSE11p53R175H), were continuously exposed to NE (100 nM, 1 μM, 10 μM). Fallopian tube cells displayed a p53-independent increase in proliferation and colony-forming ability in response to NE, while ovarian surface epithelial cells displayed a p53-independent decrease in both assays. Fallopian tube cells with mutant p53 showed a mild loss of chromosomes and TP53 status was also a defining factor in transcriptional response of fallopian tube cells to long-term NE treatment.
Highlights
Sustained adrenergic stimulation by norepinephrine (NE) contributes to ovarian carcinoma metastasis and impairment of chemotherapy response
Psychosocial stress has been associated with cancer progression in several settings[3,4,5]
We evaluated the long-term in vitro effects of norepinephrine (NE) treatment using a model of isogenic cells postulated to be the precursors of ovarian cancer—the fallopian tube epithelial cells and ovarian surface epithelial cells[15,16,17,18], which share tissue-specific signatures and transcription regulatory a rchitecture[28], and isogenic cell lines with oncogenic dominant-negative mutant p53 p.R175H to assess the extent to which p53 status influences transcriptional responses after long-term exposure to NE
Summary
Sustained adrenergic stimulation by norepinephrine (NE) contributes to ovarian carcinoma metastasis and impairment of chemotherapy response. To determine the extent to which stress hormones influence ovarian cancer initiation, we conducted a long-term (> 3 months; > 40 population doublings) experiment in which normal immortalized fallopian tube secretory (iFTSEC283) and ovarian surface epithelial (iOSE11) cell lines and their isogenic pairs containing a p53 mutation (iFTSEC283p53R175H; iOSE11p53R175H), were continuously exposed to NE (100 nM, 1 μM, 10 μM). Epithelial cell lines in tissue culture were continuously exposed to NE They were evaluated for changes in morphology, proliferation, colony-forming ability, number of chromosomes and transcriptomics. These cell lines represent a model of normal precursors cells that give rise to high grade serous ovarian carcinoma (HGSOC)[10,11,12,13]. Because TP53 alterations are highly prevalent and happen early in the development of H GSOC20,21, we evaluated exposure to continuous NE in fallopian tube and ovarian epithelial isogenic cell derivatives expressing a dominant-negative TP53 mutant (p.R175H)
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