首页|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
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
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Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor a (PPARa) is a key process by which PFOA affects the malignancy of estrogen receptor alpha (ER alpha)-positive breast cancer cells. However, there is very little information on the PPAR alpha-regulated genes responsible for the effects of PFOA in ER alpha-negative breast cancer cell malignancy. We recently demonstrated that fatty acid 2-hydroxylase (FA2H) stimulates the migration of ER alpha-negative human MDA-MB-231 cells, and PPAR alpha is a key factor for the induction of FA2H in these cells. However, evidence for the relationship between PFOA exposure and PPAR alpha-FA2H axis-driven migration has not been obtained. Here we analyzed the effects of PFOA on PPAR alpha 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 PPAR alpha. FA2H-selective siRNA, but not siRNA control, clearly dampened PFOA-mediated cell migration. There is an inhibitory interaction between PPAR alpha and PPAR beta/delta (i,e., PPAR beta/delta can suppress PPAR alpha-mediated transcription) in MDA-MB-231 cells, but even in the presence of PPAR beta/delta expression, PFOA appeared to free PPAR alpha to upregulate FA2H. Collectively, our findings show that i) PFOA activates PPAR alpha-mediated transcription, ii) PFOA stimulates migration dependent on FA2H expression, and iii) mechanistically, PFOA relieves PPAR beta/delta suppression of PPAR alpha activity to upregulate FA2H in MDA-MB-231 cells.
PFOAFA2HPPAR alphaMDA-MB-231 cellsTNBCER alpha-negative breast cancerPROLIFERATOR-ACTIVATED RECEPTORSPPAR-ALPHAPERFLUOROALKYL ACIDSGENEMOUSEGAMMAMCF-7
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