Changes in metabolism affect expression of ABC transporters through ERK5 and depending on p53 status

Area of Science:

• Cellular metabolism
• Molecular biology
• Cancer research

Background:

• ABC transporters facilitate metabolite and drug transport across cell membranes.
• Metabolic reprogramming is a hallmark of cancer, influencing drug resistance.
• p53 protein status is critical in cellular responses to metabolic stress.

Purpose of the Study:

• To investigate the impact of metabolic shifts to oxidative phosphorylation (OXPHOS) on ABC transporter expression.
• To determine the role of p53 status in regulating ABC transporter expression during metabolic changes.
• To elucidate the signaling pathways involved in p53-dependent regulation of ABC transporters.

Main Methods:

• Treating cells with dichloroacetate (DCA) or altering substrates to induce OXPHOS.
• Analyzing ABC transporter gene expression (ABCB1, ABCC1, ABCC5, ABCG2) in wild-type and mutant p53 cells.
• Investigating the role of the MAPK ERK5 signaling pathway and transcription factors MEF2, NRF1, NRF2.
• Assessing drug clearance in cells with different metabolic states and p53 status.

Main Results:

• OXPHOS reduced ABC transporter expression in wild-type p53 cells but increased it in mutant/null p53 cells.
• DCA treatment inhibited ABC transporter expression in vivo.
• Wild-type p53 cells showed impaired drug clearance under OXPHOS, while mutant p53 cells showed increased clearance.
• The ERK5/MEF2 pathway was identified as a key regulator of ABC transporter expression, dependent on p53 status.

Conclusions:

• Metabolic reprogramming to OXPHOS differentially regulates ABC transporters based on p53 integrity.
• p53 status dictates the effect of OXPHOS on drug transport and resistance.
• The ERK5/MEF2 pathway is a critical mediator of metabolic control over ABC transporter expression and function.