Perfluorooctanoic acid (PFOA) as a stimulator of estrogen receptor-negative breast cancer MDA-MB-231 cell aggressiveness: Evidence for involvement of fatty acid 2-hydroxylase (FA2H) in the stimulated cell migration
Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. However, there is very...
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Published in | Journal of toxicological sciences Vol. 47; no. 4; pp. 159 - 168 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Japan
The Japanese Society of Toxicology
01.01.2022
Japan Science and Technology Agency |
Subjects | |
Online Access | Get full text |
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Summary: | Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. However, there is very little information on the PPARα-regulated genes responsible for the effects of PFOA in ERα-negative breast cancer cell malignancy. We recently demonstrated that fatty acid 2-hydroxylase (FA2H) stimulates the migration of ERα-negative human MDA-MB-231 cells, and PPARα is a key factor for the induction of FA2H in these cells. However, evidence for the relationship between PFOA exposure and PPARα-FA2H axis-driven migration has not been obtained. Here we analyzed the effects of PFOA on PPARα transcription and FA2H expression in relation to MDA-MB-231 cell migration. We found that simultaneously with stimulated migration, PFOA upregulated FA2H and activated the transcription of PPARα. FA2H-selective siRNA, but not siRNA control, clearly dampened PFOA-mediated cell migration. There is an inhibitory interaction between PPARα and PPARβ/δ (i.e., PPARβ/δ can suppress PPARα-mediated transcription) in MDA-MB-231 cells, but even in the presence of PPARβ/δ expression, PFOA appeared to free PPARα to upregulate FA2H. Collectively, our findings show that i) PFOA activates PPARα-mediated transcription, ii) PFOA stimulates migration dependent on FA2H expression, and iii) mechanistically, PFOA relieves PPARβ/δ suppression of PPARα activity to upregulate FA2H in MDA-MB-231 cells. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0388-1350 1880-3989 |
DOI: | 10.2131/jts.47.159 |