Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also...

Area of Science:

• Oncology
• Cellular Metabolism
• Biochemistry

Background:

• Cancer cells exhibit dysregulated metabolism, with few identified druggable targets.
• Increased fatty acid (FA) uptake supports cancer cell growth but is toxic to normal cells.
• Understanding cancer's adaptation to excess FAs may reveal novel therapeutic strategies.

Purpose of the Study:

• To investigate the role of diacylglycerol O-acyltransferase 1 (DGAT1) in melanoma's adaptation to fatty acids.
• To explore DGAT1 as a potential therapeutic target in melanoma.
• To identify synergistic therapeutic strategies targeting lipid metabolism and oxidative stress.

Main Methods:

• Assessed DGAT1 expression in melanoma.
• Utilized zebrafish models to study DGAT1's role in melanoma development.
• Investigated the effects of DGAT1 antagonism and combined inhibition with superoxide dismutase 1 (SOD1).

Main Results:

• DGAT1 is frequently upregulated in melanoma, enabling tolerance to excess FA.
• DGAT1 overexpression transforms p53-mutant zebrafish melanocytes and accelerates melanoma formation with oncogenic drivers.
• DGAT1 inhibition induces oxidative stress, which melanoma cells counter by upregulating reactive oxygen species defenses.
• Combined inhibition of DGAT1 and SOD1 profoundly suppresses tumor growth by inducing overwhelming oxidative stress.

Conclusions:

• DGAT1 is a key mediator of fatty acid tolerance and oncogenesis in melanoma.
• Targeting DGAT1 presents a promising therapeutic avenue for melanoma.
• Dual inhibition of DGAT1 and SOD1 offers a potent strategy to eradicate melanoma by overwhelming cancer cells with oxidative stress.