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Exploring Rapamycin-induced Pro-survival Pathways in Tuberous Sclerosis Complex and the Development of Alternative Therapies

Lu, Yiyang
http://orcid.org/0000-0002-3929-1744
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613752713277464

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Pathobiology and Molecular Medicine.
Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disease with multi-system manifestations including benign neoplastic growth in the brain, heart, kidneys, and lung. Inactivating gene mutations in either TSC1 or TSC2 result in hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1), which leads to the uncontrolled cell growth and proliferation in TSC. Lymphangioleiomyomatosis (LAM) is the lung manifestation of TSC and can also present as sporadic form. It occurs predominantly in women during their reproductive age and is exacerbated by female hormones including estrogen, progesterone and prolactin. To explore the underlying molecular mechanism of this hormonal predominance, we utilized TSC2-deficient models and showed that estrogen promotes glycolytic metabolism in tumor cells through activation of pyruvate kinase muscle isozyme M2 (PKM2). Accumulation of phosphorylated PKM2 was evident in pulmonary nodule and renal angiomyolipoma cells from LAM patients. These data suggest that the female predominance of LAM might partially be attributed to estrogen stimulation of PKM2-mediated cellular metabolic alterations. The clinical application of mTORC1 specific inhibitors (mTORi), including sirolimus (rapamycin) and everolimus, have been shown to promote tumor regression and stabilize lung function in TSC and LAM patients. However, sustained improvement requires continuous exposure, as refractory growth occurs upon drug cessation, suggesting a cytostatic rather than a cytocidal nature of the medicine. We recapitulated rapamycin- induced refractory response in mouse xenograft tumors. RNA sequencing analysis of xenograft tumors from different growth stages revealed upregulation of pro-survival mitogen activated protein kinase (MAPK) pathway under rapamycin induction. This studyrevealed a MAPK-evoked positive feedback loop that dampens the efficacy of mTOR inhibition in TSC models. Pharmacological inhibition of MAPK abrogated this feedback loop activation, and combinatorial inhibition of mTOR and MAPK induced death of TSC2- deficient cells. Collectively, our results revealed novel survival mechanisms in TSC2-deficient models and provide a proof of concept for the development of remission-inducing therapies for TSC and LAM patients.
Phillip Owens, Ph.D. (Committee Chair)
Tanya Kalin, M.D. Ph.D. (Committee Member)
Mario Medvedovic, Ph.D. (Committee Member)
Manoocher Soleimani, M.D. (Committee Member)
Yan Xu, Ph.D. (Committee Member)
88 p.
Surgery
Tuberous Sclerosis Complex; Lymphangioleiomyomatosis; mTOR; Estrogen; PKM2; MAPK

Recommended Citations

Citations

  • Lu, Y. (2020). Exploring Rapamycin-induced Pro-survival Pathways in Tuberous Sclerosis Complex and the Development of Alternative Therapies [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613752713277464

    APA Style (7th edition)

  • Lu, Yiyang. Exploring Rapamycin-induced Pro-survival Pathways in Tuberous Sclerosis Complex and the Development of Alternative Therapies. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613752713277464.

    MLA Style (8th edition)

  • Lu, Yiyang. "Exploring Rapamycin-induced Pro-survival Pathways in Tuberous Sclerosis Complex and the Development of Alternative Therapies." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1613752713277464

    Chicago Manual of Style (17th edition)

ucin1613752713277464
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This open access ETD is published by University of Cincinnati and OhioLINK.