Flavin dependency undermines proteome stability, lipid metabolism and cellular proliferation during vitamin B2...

Area of Science:

• Biochemistry
• Oncology
• Metabolic pathways

Background:

• Tumor cells exhibit metabolic adaptations for growth and invasiveness, leading to dependencies on specific metabolic pathways.
• Targeting individual metabolic nodes is a therapeutic strategy, but simultaneous targeting of multiple enzymes remains challenging.
• Flavin-containing enzymes (flavoproteome) are crucial for numerous biotransformations in mammalian cells.

Purpose of the Study:

• To investigate the consequences of flavoproteome inactivation in melanoma cells.
• To explore the potential of targeting flavoenzymes for cancer therapy.
• To identify vulnerabilities created by disrupting flavin metabolism.

Main Methods:

• Restricted riboflavin (vitamin B2) supply to induce flavin deficiency in melanoma cells.
• Assessed protein stability and proteostasis network interactions using mass spectrometry.
• Performed proteome-wide analysis to identify affected metabolic pathways.

Main Results:

• Vitamin B2 deficiency destabilized numerous proteins, mimicking HSP90 inhibition and engaging proteostasis networks.
• Flavin depletion led to the inactivation of the mevalonate pathway, crucial for cholesterol synthesis.
• Riboflavin-starved tumor cells exhibited cell cycle arrest and increased sensitivity to alkylating chemotherapy.

Conclusions:

• The flavoproteome represents a viable target for cancer therapy.
• Flavoproteome inactivation creates synthetic lethality vulnerabilities by disrupting metabolism and proteostasis.
• Combining proteostasis manipulation with metabolic reprogramming offers a promising therapeutic strategy.