Phospholipid Scramblase 1, an interferon-regulated gene located at 3q23, is regulated by SnoN/SkiL in ovarian cancer cells
© Kodigepalli et al.; licensee BioMed Central Ltd. 2013
Received: 22 January 2013
Accepted: 17 April 2013
Published: 26 April 2013
Treatment of advanced stage ovarian cancer continues to be challenging due to acquired drug resistance and lack of early stage biomarkers. Genes identified to be aberrantly expressed at the 3q26.2 locus (i.e. SnoN/SkiL) have been implicated in ovarian cancer pathophysiology. We have previously shown that SnoN expression is increased in advanced stage ovarian cancers and alters cellular response to arsenic trioxide (As2O3).
We now demonstrate increased DNA copy number levels (TCGA data) of phospholipid scramblase 1 (PLSCR1, located at 3q23) whose transcript expression in ovarian cell lines is highly correlated with SnoN mRNA. Interestingly, SnoN can modulate PLSCR1 mRNA levels in the absence/presence of interferon (IFN-2α). Both IFN-2α and As2O3 treatment can modulate PLSCR1 mRNA levels in ovarian carcinoma cells. However, SnoN siRNA does not lead to altered PLSCR1 protein implicating other events needed to modulate its protein levels. In addition, we report that PLSCR1 can modulate aspects of the As2O3 cellular response.
Our findings warrant further investigation into the role of PLSCR1 in ovarian cancer development and chemoresistance.
KeywordsSnoN/SkiL Phospholipid scramblase PLSCR1 Arsenic trioxide Interferon TGF-β 3q26.2 3q23 Ovarian cancer
Phospholipid Scramblase 1
Ski Related Novel Protein N
Ecotropic Viral Integration Site-1
phosphatidylinositol-3-kinase catalytic subunit-α
Protein Kinase C iota
Array Comparative Genomic Hybridization
The Cancer Genome Atlas
Plasminogen Activator Inhibitor-1
Transforming Growth Factor-β
Reactive Oxygen Species
Microtubule-associated protein light chain 3
Green fluorescent protein
Poly-ADP Ribose Polymerase
Immortalized (LTAg/hTERT) normal ovarian surface epithelial cells
Acute Promyelocytic Leukemia.
Epithelial ovarian cancer represents the most common gynecological cancer in women with an unfortunate high mortality rate due to acquired chemotherapeutic resistance . Our earlier published studies indicate that the 3q26.2 chromosomal region is highly amplified in ovarian cancers  and harbors various oncogenes including EVI1 , PKCι , and SnoN/SkiL . In particular, we previously demonstrated that SnoN, a negative transcriptional regulator of TGFβ signaling, modulates the pro-survival autophagic pathway in response to arsenic trioxide (As2O3), a chemotherapeutic agent used in the treatment of acute promyelocytic leukemia (APL) . Interestingly, there are reports which indicate that genes located at and proximal to the 3q26 locus may regulate each other. For instance, both EVI1 and PIK3CA can regulate SnoN expression [6, 7]. Herein, we now report that the expression of phospholipid scramblase 1 (PLSCR1), located at 3q23, can be modulated via SnoN. PLSCR1 has been implicated in maintaining plasma membrane lipid asymmetry, regulating growth factor signaling pathways, in modulating tumor growth in mouse xenograft models , and cancer development [9, 10]. The role of PLSCR1 in ovarian cancer and in modulating response to chemotherapeutic agents has yet to be fully understood.
In the current study, we demonstrate that PLSCR1 and SnoN DNA copy number as well as their RNA levels are correlated. By modulating SnoN expression, PLSCR1 mRNA levels appear to be co-regulated (Figure 4G). Of interest, SnoN knockdown does not alter PLSCR1 protein possibly suggesting that other mediators are involved in its regulation. Nonetheless, similar to SnoN, reduction in PLSCR1 levels appears to increase the cellular sensitivity to As2O3. Whether PLSCR1 modulates sensitivity to carboplatin/paclitaxel or whether the effects of As2O3 and TGFβ are mediated via IFN remain to be investigated. Thus, further investigations are warranted to delve into the significance of these findings in ovarian cancer development and chemoresistance.
This work was supported by funds from the National Institute of Health RO1 CA 123219 and University of South Florida Start-up Funds to Meera Nanjundan. This work was also supported in part by the Flow Cytometry Core Facility at the College of Medicine, University of South Florida. We thank Dawn Smith, Annemarie Boland, and Hussain Basrawala for their technical assistance with the studies presented herein. We also are grateful to Stephanie Rockfield and Katherine Allen for their assistance with figure preparation.
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