Leucyl-tRNA synthetase 1 is required for proliferation of TSC-null cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Cancer cell proliferation is often driven by the loss of tumor suppressor functions.
• The tuberous sclerosis complex (TSC) normally suppresses cell growth by inhibiting mTORC1 in response to nutrients.
• The precise mechanisms governing nutrient-dependent proliferation in TSC-null cells are not fully understood.

Purpose of the Study:

• To elucidate the nutrient-dependent cell proliferation mechanisms in tuberous sclerosis complex-null (TSC-null) cells.
• To investigate the role of leucine and the leucyl-tRNA synthetase (LARS1)-mTORC1 pathway in TSC-null cell growth.
• To explore potential therapeutic strategies targeting this pathway.

Main Methods:

• Investigated cell proliferation and survival in TSC-null cells under various conditions.
• Utilized LARS1 knock-down and specific inhibitors.
• Assessed colony formation ability with rapamycin and LARS1 inhibitors, both individually and in combination.

Main Results:

• Leucine was found to be essential for cell proliferation in TSC-null cells, mediated by the LARS1-mTORC1 pathway.
• Knock-down or inhibition of LARS1 significantly reduced cell proliferation and survival in TSC-null cells.
• Both rapamycin and LARS1 inhibitors impaired colony formation, with combined treatment showing a drastic reduction.

Conclusions:

• Leucine activates the LARS1-mTORC1 pathway, promoting cell proliferation and survival in TSC-null cells.
• LARS1 inhibitors show promise as novel therapeutic agents for TSC-null tumors, potentially overcoming resistance to mTORC1 inhibition.
• Targeting the LARS1-mTORC1 axis offers a potential strategy for managing tumor regrowth after initial mTORC1 inhibition therapy.