BMAL1 Drives Cisplatin Resistance in Non-Small Cell Lung Cancer Via Lactate-MRP1 Signaling Pathway

Area of Science:

• Molecular Biology
• Oncology
• Chronobiology

Background:

• Lung cancer exhibits high mortality, with chemoresistance posing a major therapeutic hurdle.
• Metabolic reprogramming and circadian rhythm disruptions are linked to tumor progression, but their role in chemoresistance is not fully understood.

Purpose of the Study:

• To investigate the role of the circadian regulator BMAL1 in cisplatin resistance in non-small cell lung cancer (NSCLC).
• To elucidate the underlying metabolic and oxidative stress pathways involved in BMAL1-mediated chemoresistance.

Main Methods:

• Investigated BMAL1's role in NSCLC chemoresistance.
• Analyzed the upregulation of multidrug resistance protein MRP1 via HIF-1α-driven glycolysis and lactate production.
• Examined the activation of the TAZ/c-Jun/Snail complex by lactate.
• Studied the induction of BMAL1 by cisplatin and etoposide through AKT signaling in response to oxidative stress.

Main Results:

• BMAL1 was identified as a key driver of cisplatin resistance in NSCLC.
• BMAL1 upregulates MRP1 through HIF-1α-driven glycolysis, increasing lactate production, which further enhances MRP1 expression via the TAZ/c-Jun/Snail complex, creating a resistance loop.
• Cisplatin and etoposide induce BMAL1 via AKT signaling in response to oxidative stress, reinforcing resistance.
• Targeting AKT or MRP1 effectively reversed BMAL1-mediated chemoresistance.

Conclusions:

• BMAL1 acts as a metabolic orchestrator connecting circadian dysfunction to chemoresistance in NSCLC.
• Targeting the crosstalk between circadian rhythms and metabolism, specifically via AKT inhibition or chronotherapy, presents promising strategies to overcome therapeutic failure in NSCLC.
• This study highlights the importance of considering circadian-metabolic pathways for improved lung cancer treatment outcomes.