Targeting FOXM1 regulates metabolic signatures through ROS-dependent JNK/Bmi1/Skp2 axis in human cutaneous T-cell...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Cutaneous T-cell lymphoma (CTCL) is a complex cancer with poor prognosis due to metabolic reprogramming and cancer stemness.
• Limited therapeutic options necessitate understanding CTCL's underlying mechanisms.
• Forkhead box protein M1 (FOXM1) is an oncogenic factor driving cancer progression, metabolic changes, and treatment resistance.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting FOXM1 in human CTCL cells.
• To elucidate the mechanisms by which FOXM1 inhibition affects CTCL cell growth, metabolism, and stemness.

Main Methods:

• Genetic and pharmacological inhibition of FOXM1 in CTCL cell lines.
• Assessment of cell viability, proliferation, and programmed cell death (apoptosis and autophagy).
• Analysis of reactive oxygen species (ROS) generation, MAPK/JNK signaling pathway activation, and metabolomics.
• Evaluation of stemness markers and proteasome inhibitor sensitivity.

Main Results:

• FOXM1 inhibition significantly suppressed CTCL cell growth and proliferation.
• Targeting FOXM1 induced apoptosis and autophagy via ROS generation and JNK activation.
• Metabolomics revealed ROS- and JNK-dependent alterations in amino acid and lipid metabolism.
• FOXM1 inhibition reduced stemness markers (KLF-4, Bmi1, Skp2) and increased p21 expression in a JNK-dependent manner.
• Thiostrepton treatment sensitized CTCL cells to bortezomib, enhancing cell death.

Conclusions:

• FOXM1 inhibition is a promising therapeutic strategy for CTCL.
• Targeting FOXM1 disrupts CTCL cell metabolism and stemness through ROS and JNK signaling.
• This approach offers potential to overcome therapeutic resistance in CTCL.