title: Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis.
abstract: 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.
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Erik
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Po-Shun
authors.initials: PS
authors.lastname: Lee
authors.affiliation: Peking Union Medical College, Beijing, China.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Osorio
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.affiliation: Peking Union Medical College, Beijing, China.
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Xu
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D018207:Angiomyolipoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055786:Gene Knockout Techniques; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D018192:Lymphangioleiomyomatosis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D054467:Phospholipases A2 / Q000235:genetics*; D020123:Sirolimus / Q000494:pharmacology*; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D054467:Phospholipases A2; D020123:Sirolimus