We report a negative feedback loop between the signaling
protein phospholipase D (
PLD),
phosphatidic acid (PA), and a specific set of
microRNAs (
miRNAs) during nutrient
starvation of
breast cancer cells. We show that
PLD expression is increased in four
breast cancer cell lines and that hypoxia, cell overcrowding, and nutrient
starvation for 3 to 6 h increase expression even further. However, after prolonged (>12-h)
starvation,
PLD levels return to basal or lower levels. The mechanism for this is as follows. First, during initial
starvation, an elevated PA (the product of
PLD enzymatic activity) activates mTOR and S6K, known to inhibit apoptosis, and enhances cell migration especially in post-epithelial-to-mesenchymal transition (post-EMT)
cancer cells. Second, continued PA production in later
starvation induces expression of
PLD-targeting
microRNA 203 (miR-203), miR-887, miR-3619-5p, and miR-182, which reduce
PLD translation. We provide direct evidence for a feedback loop, whereby
PLD induction upon
starvation leads to PA, which induces expression of
miRNAs, which in turn inhibits PLD2 translation. The physiological relevance for
breast cancer cells is that as PA can activate cell invasion, then, due to the negative feedback, it can deprive mTOR and S6K of their natural activator. It can further prevent inhibition of apoptosis and allow cells to survive nutrient deprivation, which normal cells cannot do.