Tuberous sclerosis syndrome (
TSC) is an autosomal dominant tumor suppressor gene syndrome affecting multiple organs, including renal
angiomyolipomas and pulmonary
lymphangioleiomyomatosis (
LAM).
LAM is a female-predominant
interstitial lung disease characterized by the progressive
cyst formation and
respiratory failure, which is also seen in sporadic patients without
TSC. Mutations in TSC1 or TSC2 cause
TSC, result in hyperactivation of
mammalian target of rapamycin (mTOR), and are also seen in
LAM cells in sporadic
LAM. We recently reported that
prostaglandin biosynthesis and
cyclooxygenase-2 were deregulated in
TSC and
LAM.
Phospholipase A2 (PLA2) is the rate-limiting
enzyme that catalyzes the conversion of plasma membrane
phospholipids into
prostaglandins. In this study, we identified upregulation of adipocyte AdPLA2 (PLA2G16) in
LAM nodule cells using publicly available expression data. We showed that the levels of AdPLA2 transcript and
protein were higher in
LAM lungs compared with control lungs. We then showed that TSC2 negatively regulates the expression of AdPLA2, and loss of TSC2 is associated with elevated production of
prostaglandin E2 (
PGE2) and
prostacyclin (PGI2) in cell culture models. Mouse model studies also showed increased expression of AdPLA2 in xenograft
tumors,
estrogen-induced lung metastatic lesions of Tsc2 null
leiomyoma-derived cells, and spontaneous renal
cystadenomas from Tsc2+/- mice. Importantly,
rapamycin treatment did not affect the expression of AdPLA2 and the production of
PGE2 by TSC2-deficient mouse embryonic fibroblast (Tsc2-/-MEFs), rat uterine
leiomyoma-derived ELT3 cells, and
LAM patient-associated renal
angiomyolipoma-derived "mesenchymal" cells. Furthermore, methyl arachidonyl
fluorophosphate (MAFP), a potent irreversible PLA2 inhibitor, selectively suppressed the growth and induced apoptosis of TSC2-deficient
LAM patient-derived cells relative to TSC2-addback cells. Our findings suggest that AdPLA2 plays an important role in promoting
tumorigenesis and
disease progression by modulating the production of
prostaglandins and may serve as a potential therapeutic target in
TSC and
LAM.