Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells.

[lymphangioleiomyomatosis]

Lymphangioleiomyomatosis (LAM ) is a female -predominant interstitial lung disease that can lead to respiratory failure . LAM cells typically have inactivating TSC 2 mutations , leading to mTORC 1 activation . The gender specificity of LAM suggests that estradiol contributes to disease development , yet the underlying pathogenic mechanisms are not completely understood . Using metabolomic profiling , we identified an estradiol-enhanced pentose phosphate pathway signature in Tsc 2 -deficient cells . Estradiol increased levels of cellular NADPH , decreased levels of reactive oxygen species , and enhanced cell survival under oxidative stress . Mechanistically , estradiol reactivated Akt in TSC 2 -deficient cells in vitro and in vivo , induced membrane translocation of glucose transporters (GLUT 1 or GLUT 4 ), and increased glucose uptake in an Akt-dependent manner . (18 )F-FDG-PET imaging demonstrated enhanced glucose uptake in xenograft tumors of Tsc 2 -deficient cells from estradiol-treated mice . Expression array study identified estradiol-enhanced transcript levels of glucose-6 -phosphate dehydrogenase (G 6 PD ), the rate-limiting enzyme of the pentose phosphate pathway . Consistent with this , G 6 PD was abundant in xenograft tumors and lung metastatic lesions of Tsc 2 -deficient cells from estradiol-treated mice . Molecular depletion of G 6 PD attenuated estradiol-enhanced survival in vitro , and treatment with 6 -aminonicotinamide , a competitive inhibitor of G 6 PD , reduced lung colonization of Tsc 2 -deficient cells . Collectively , these data indicate that estradiol promotes glucose metabolism in mTORC 1 hyperactive cells through the pentose phosphate pathway via Akt reactivation and G 6 PD upregulation , thereby enhancing cell survival under oxidative stress . Interestingly , a strong correlation between estrogen exposure and G 6 PD was also found in breast cancer cells . Targeting the pentose phosphate pathway may have therapeutic benefit for LAM and possibly other hormonally dependent neoplasms .

Diseases
Validation

Diseases presenting "deficient cells" symptom

child syndrome

esophageal adenocarcinoma

gm1 gangliosidosis

junctional epidermolysis bullosa

kindler syndrome

lymphangioleiomyomatosis

neonatal adrenoleukodystrophy

werner syndrome

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