mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol...

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• The mechanistic target of rapamycin (mTOR) pathway critically regulates cellular lipid homeostasis.
• Dysregulation of mTOR and lipid metabolism is implicated in various diseases, notably cancers.
• Understanding mTOR's role in reprogramming lipid metabolism is vital for therapeutic development.

Purpose of the Study:

• To elucidate the mechanisms by which mTOR inhibition alters lipid homeostasis in cancer cells.
• To identify key molecular players involved in mTOR-mediated lipid reprogramming.
• To evaluate the therapeutic potential of targeting these pathways in cancer models.

Main Methods:

• Utilized human cancer cell lines to study mTOR inhibition effects on lipid metabolism.
• Investigated the roles of eukaryotic initiation factor 3D (eIF3D), low-density lipoprotein receptor-related protein 6 (LRP6), liver X receptor β (LXRβ), and Niemann-Pick disease type C (NPC) intracellular cholesterol transporter 1 (NPC1).
• Employed mouse xenograft models to assess therapeutic efficacy of combined mTOR inhibition with LRP6 or NPC1 targeting.

Main Results:

• mTOR inhibition in cancer cells upregulates LRP6 via eIF3D, enhancing lipid uptake.
• Activated LXRβ promotes cholesterol transport from lysosomes to the plasma membrane, facilitated by NPC1.
• Combined mTOR inhibition with LRP6 knockdown or NPC1 targeting significantly suppressed tumor growth in vivo.

Conclusions:

• mTOR signaling plays a crucial feedback role in reprogramming lipid homeostasis during cancer progression.
• Targeting the identified lipid metabolism pathways (LRP6, NPC1) alongside mTOR inhibition presents a promising therapeutic strategy.
• These findings offer potential treatments for diseases characterized by aberrant mTOR signaling and lipid dysregulation.