Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells

Li, Chenggang; Lee, Po‐Shun; Sun, Yangying; Gu, Xiaoqiong; Zhang, Erik; Guo, Junming; Wu, Chin‐Lee; Auricchio, Neil; Priolo, Carmen; Li, Jing; Csibi, Alfredo; Parkhitko, Andrey A.; Morrison, Tasha; Planagumà, Anna; Kazani, Shamsah; Israel, Elliot; Xu, Kai‐Feng; Henske, Elizabeth P.; Blenis, John; Levy, Bruce D.; Kwiatkowski, David J.; Yu, Jane

doi:10.1084/jem.20131080

Cited by 60 publications

(67 citation statements)

References 43 publications

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“…Second, pulmonary and extrapulmonary LAM is characterized by abnormal blood and lymphatic vasculature, which could be influenced by bioactive lipids, including LPC. Third, up-regulation of COX2, an enzyme responsible for the production of prostaglandins downstream of PLA2, and PLA2G16 has been recently found in LAM nodules (39,40). Therefore, in addition to the PLA2-dependent proliferation demonstrated here, we hypothesize that other LPC-dependent pathways may participate in LAM pathogenesis.…”

Section: Discussionsupporting

confidence: 59%

Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis

Priolo

Ricoult

Khabibullin

et al. 2015

Am J Respir Cell Mol Biol

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Lymphangioleiomyomatosis (LAM) is a destructive lung disease affecting women. LAM is caused by mutations in the tuberous sclerosis complex (TSC) genes. The TSC protein complex inhibits the mechanistic/mammalian target of rapamycin complex 1 (mTORC1), which is a master regulator of cellular metabolism. Using mass spectrometry-based lipid profiling, we analyzed plasma from patients with LAM and discovered elevated levels of four lysophosphatidylcholine (LPC) species (C16:0, C18:0, C18:1, and C20:4) compared with those in healthy control women. To investigate whether these lipids are generated in a TSC2-dependent manner, we profiled in vitro preclinical models of TSC/LAM and found significant LPC accumulation in TSC2-deficient cells relative to TSC2-expressing control cells. These lysoglycerophospholipid changes occurred alongside changes in other phospholipid and neutral lipid species. Treatment with rapamycin or torin1 or downregulation of sterol regulatory element-binding protein (SREBP), a lipogenic transcription factor, did not suppress LPC in TSC2-deficient cells. Inhibition of distinct isoforms of phospholipase A2 decreased the proliferation of TSC2-deficient cells. Collectively, these results demonstrate that TSC2-deficient cells have enhanced choline phospholipid metabolism and reveal a novel function of the TSC proteins in choline lysoglycerophospholipid metabolism, with implications for disease pathogenesis and targeted therapeutic strategies.

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Section: Discussionsupporting

confidence: 59%

Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis

Priolo

Ricoult

Khabibullin

et al. 2015

Am J Respir Cell Mol Biol

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“…Sun et al reported that estradiol treatment promoted glucose metabolism via enhanced pentose phosphate pathway addiction, increased the glucose uptake in vitro via Akt reactivation, and increased the survival of LAM patient-derived cells in a G6PD-dependent manner [36]. In addition, Li et al demonstrated that estradiol treatment increased phospholipid-arachidonate breakdown, the expression of COX-2, and the production of prostaglandin metabolites in LAM patient-derived cells [34]. In this study, the effects of E 2 and/or Pg on cell proliferation and survival are subtle, but we repeatedly observe similar trends.…”

Section: Discussionmentioning

confidence: 99%

Progesterone and Estradiol Synergistically Promote the Lung Metastasis of Tuberin-Deficient Cells in a Preclinical Model of Lymphangioleiomyomatosis

et al. 2014

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Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 hyperactivation. The gender specificity of LAM suggests that female hormones contribute to disease progression. Clinical findings indicate that estradiol exacerbates LAM behaviors and symptoms. Although hormonal therapy with progesterone has been employed, the benefit in LAM improvement has not been achieved. We have previously found that estradiol promotes the survival and lung metastasis of cells lacking tuberin in a preclinical model of LAM. In this study, we hypothesize that progesterone alone or in combination with estradiol promote metastatic behaviors of TSC2-deficient cells. In cell culture models of TSC2-deficient LAM patient-derived and rat uterine leiomyoma-derived cells, we found that progesterone treatment or progesterone plus estradiol resulted in increased phosphorylation of Akt and ERK1/2, induced the proliferation, and enhanced the migration and invasiveness. In addition, treatment of progesterone plus estradiol synergistically decreased the levels of reactive oxygen species, and enhanced cell survival under oxidative stress. In a murine model of LAM, treatment of progesterone plus estradiol promoted the growth of xenograft tumors; however, progesterone treatment did not affect the development of xenograft tumors of Tsc2-deficient cells. Importantly, treatment of progesterone plus estradiol resulted in alteration of lung morphology, and significantly increased the number of lung micrometastases of Tsc2-deficient cells compared with estradiol treatment alone. Collectively, these data indicate that progesterone increases the metastatic potential of TSC2-deficient LAM patient-derived cells in vitro and lung metastasis in vivo. Thus, targeting progesterone-mediated signaling events may have therapeutic benefit for LAM and possibly other hormonally dependent cancers.

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“…Little is known about the molecular mechanisms underlying E 2 -induced survival and metastasis of tuberin-deficient cells. The impact of E 2 on the growth of tuberin-deficient cells has been reported (9,(33)(34)(35)(36)(37)(38)(39)(40). Gu et al reported that E 2 activates Erk1/2 and increases the migration and invasion of tuberin-deficient cells (41).…”

Section: Discussionmentioning

confidence: 97%

Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells

Abstract: Estradiol enhances COX-2 expression and prostaglandin biosynthesis in TSC2-deficient cells via a rapamycin-insensitive, mTORC2-dependent mechanism.

Cited by 60 publications

References 43 publications

Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis

Tuberous Sclerosis Complex 2 Loss Increases Lysophosphatidylcholine Synthesis in Lymphangioleiomyomatosis

Progesterone and Estradiol Synergistically Promote the Lung Metastasis of Tuberin-Deficient Cells in a Preclinical Model of Lymphangioleiomyomatosis

Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis

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