54 research outputs found
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Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells
Lymphangioleiomyomatosis (LAM) is a female-predominant interstitial lung disease that can lead to respiratory failure. LAM cells typically have inactivating TSC2 mutations, leading to mTORC1 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 Tsc2-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 TSC2-deficient cells in vitro and in vivo, induced membrane translocation of glucose transporters (GLUT1 or GLUT4), and increased glucose uptake in an Akt-dependent manner. 18F-FDG-PET imaging demonstrated enhanced glucose uptake in xenograft tumors of Tsc2-deficient cells from estradiol-treated mice. Expression array study identified estradiol-enhanced transcript levels of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. Consistent with this, G6PD was abundant in xenograft tumors and lung metastatic lesions of Tsc2-deficient cells from estradiol-treated mice. Molecular depletion of G6PD attenuated estradiol-enhanced survival in vitro, and treatment with 6-aminonicotinamide, a competitive inhibitor of G6PD, reduced lung colonization of Tsc2-deficient cells. Collectively, these data indicate that estradiol promotes glucose metabolism in mTORC1 hyperactive cells through the pentose phosphate pathway via Akt reactivation and G6PD upregulation, thereby enhancing cell survival under oxidative stress. Interestingly, a strong correlation between estrogen exposure and G6PD was also found in breast cancer cells. Targeting the pentose phosphate pathway may have therapeutic benefit for LAM and possibly other hormonally dependent neoplasms
Survival of A-group and B-group Leptosphaeria maculans (phoma stem canker) ascospores in air and mycelium on oilseed rape stem debris
Mycelium of Leptosphaeria maculans survived on oilseed rape stem base debris buried in sand for 2, 4, 6, 8, 10 or 12 months and produced pseudothecia after subsequent exposure on the surface of the ground under natural conditions for 2-4 months, but did not survive on upper stem debris buried for 2 months. Only A-group L. maculans ascospores were produced on the stem base debris which had been buried; no B-group ascospores were produced. Mycelium of L. maculans survived on both stem base and upper stem debris exposed on the sand surface for 2, 4, 6, 8, 10 or 12 months and pseudothecia with viable ascospores were observed at the time of sampling. Both A-group L. maculans (predominant on stem bases) and B-group L. maculans (predominant on upper stems) ascospores were produced on unburied stem base and upper stem debris. Thus B-group L. maculans survived longer on unburied debris than on buried debris. A-group ascospores which were exposed in dry air in darkness at 5-20degreesC survived longer than B-group ascospores; 10-37% of A-group ascospores, compared with 2-31% of B-group ascospores, survived after 35 days.Peer reviewe
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