Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis

Area of Science:

• Pulmonology
• Oncology
• Endocrinology

Background:

• Lymphangioleiomyomatosis (LAM) is a rare, destructive lung disease primarily affecting women, characterized by tuberin-null cells with hyperactive mTORC1 signaling.
• Current treatments using mTORC1 inhibitors like rapamycin show limited efficacy, highlighting the need for novel therapeutic strategies.
• The exacerbation of LAM during pregnancy suggests a potential role for estrogen (E2) in disease pathogenesis.

Purpose of the Study:

• To investigate the role of estrogen (E2) in the molecular mechanisms underlying LAM progression.
• To explore the interplay between E2-mediated signaling and mTORC1 activity in LAM pathogenesis.
• To identify potential combination therapeutic targets for LAM.

Main Methods:

• Utilized a LAM patient-derived cell line with biallelic Tuberin inactivation.
• Assessed the effects of E2 on ERK2 activation and Fra1 gene transcription.
• Investigated the role of mTORC1/S6K1 signaling in enhancing Fra1 translation via eukaryotic translation initiation factor 4B phosphorylation.

Main Results:

• E2 induced a robust, biphasic activation of ERK2 and transcription of the epithelial-to-mesenchymal transition-associated gene Fra1.
• Activated mTORC1/S6K1 signaling enhanced the efficiency of Fra1 mRNA translation.
• This enhancement occurred through the phosphorylation of S6K1-dependent eukaryotic translation initiation factor 4B.

Conclusions:

• Estrogen (E2) signaling, through the ERK2 pathway, cooperates with mTORC1 signaling to promote LAM progression.
• The combined targeting of the E2-ERK pathway and the mTORC1 pathway presents a promising therapeutic strategy for LAM.
• Further research into this synergistic interaction could lead to more effective treatments for patients with LAM.