Inhibition of amino acid transporter LAT1 in cancer cells suppresses G0/G1-S transition by downregulating cyclin D1...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Cell Biology

Background:

• L-type amino acid transporter 1 (LAT1) is crucial for cancer cell growth and is upregulated in many cancers.
• Nanvuranlat (Nanv) is a selective LAT1 inhibitor designed to target cancer cell proliferation.
• The precise molecular mechanisms by which Nanv induces cell cycle arrest remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying Nanv-induced G0/G1 cell cycle arrest in pancreatic cancer cells.
• To investigate the role of p38 MAPK and cyclin D1 in Nanv's anti-cancer effects.

Main Methods:

• Pancreatic cancer cells were synchronized at the G0/G1 checkpoint using serum deprivation.
• Cells were treated with Nanvuranlat (Nanv) and released to assess cell cycle progression.
• p38 MAPK activation, cyclin D1 phosphorylation, and proteasomal degradation were analyzed.
• Isoform-specific knockdown of p38 MAPK and treatment with proteasome inhibitors were employed.
• Effects were validated in Nanv-treated xenograft tumor models.

Main Results:

• Nanvuranlat (Nanv) treatment significantly blocked the G0/G1 to S phase transition in pancreatic cancer cells.
• This blockade was associated with sustained p38 MAPK activation and subsequent proteasomal degradation of cyclin D1.
• p38α MAPK was identified as the predominant isoform involved.
• Proteasome inhibition restored cyclin D1 levels and released the Nanv-induced cell cycle arrest.
• These molecular events were mirrored in vivo in xenograft tumor models.

Conclusions:

• Nanvuranlat (Nanv) effectively inhibits cancer cell cycle progression by inducing p38α MAPK-dependent degradation of cyclin D1.
• This study provides critical insights into the molecular basis of amino acid-dependent cell cycle checkpoints.
• The findings support the therapeutic potential of LAT1 inhibitors like Nanv in cancer treatment.