Tuberin Regulates Prostaglandin Receptor-Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Tuberous sclerosis complex (TSC) is a genetic disorder characterized by tumor formation across multiple organs due to mutations in TSC1 or TSC2 genes.
• These mutations lead to the hyperactivation of the mTOR complex 1 (mTORC1) pathway, a key regulator of cell growth and proliferation.
• Current treatments using mTORC1 inhibitors show limited efficacy and uncertain long-term outcomes, necessitating exploration of alternative therapeutic targets.

Purpose of the Study:

• To investigate the role of prostaglandin E2 (PGE2) and its receptors in TSC pathogenesis.
• To identify novel therapeutic targets beyond direct mTORC1 inhibition for TSC treatment.
• To elucidate the regulatory mechanisms of EP3 expression in TSC2-deficient cells.

Main Methods:

• Analysis of EP3 (PTGER3) expression in TSC2-deficient cells and patient-derived tissues (angiomyolipomas, lymphangioleiomyomatosis nodules, brain tubers).
• Investigation of the regulatory role of TSC2 and Rheb in EP3 expression using cell culture models.
• Assessment of the therapeutic potential of an EP3 antagonist (L-798106) in vitro and in vivo models of TSC.

Main Results:

• EP3 expression was significantly upregulated in TSC2-deficient cells and various TSC-associated tumors.
• TSC2 loss and Rheb activation promoted EP3 expression in a manner insensitive to rapamycin.
• Inhibition of EP3 with L-798106 suppressed TSC2-deficient cell viability and reduced tumor cell lung colonization.

Conclusions:

• Aberrant upregulation of the PGE2-EP3 signaling axis is a key feature of TSC pathogenesis.
• TSC2 and Rheb play a critical role in regulating EP3 expression.
• Targeting the PGE2-EP3 pathway represents a promising therapeutic strategy for TSC and other neoplasms with mTOR hyperactivation.