Synergistic induction of colorectal cancer cell proliferation by ox-LDL and TNF-α.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Its incidence continues to rise, particularly in association with modifiable risk factors such as obesity, which is closely linked to chronic inflammation and metabolic disturbances, including dyslipidemia. These conditions contribute to the formation of a pro-inflammatory tumor microenvironment, characterized by high levels of TNF-α and ox-LDL. This study aimed to analyze the synergistic effects of ox-LDL and TNF-α on ROS production and cell proliferation via the WNT/β-catenin and PI3K/AKT pathways in CRC cells. COLO320 and SW620 cells were treated with various concentrations of ox-LDL, TNF-α, and their combinations. The proliferation induced was assessed using the IncuCyte® Real-Time Assay. ROS generation was measured using the 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) probe. Cell viability was evaluated using the MTT assay under conditions of pathway inhibition. Co-treatment with ox-LDL and TNF-α significantly increased proliferation in COLO320 cells, and was accompanied by a marked increase in ROS generation in both cell lines. Inhibiting the WNT/β-catenin and PI3K/AKT pathways revealed differential responses, suggesting a heterogeneous activation pattern dependent on the molecular context. To our knowledge, this is the first study to demonstrate the synergistic effect of ox-LDL and TNF-α in colorectal cancer cell models. These findings highlight the importance of considering both the molecular and redox context of the tumor microenvironment when designing personalized therapeutic strategies.