Suppression of macrophages- Induced inflammation via targeting RAS and PAR-4 signaling in breast cancer cell lines

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Tumor-associated macrophages (TAMs) significantly influence cancer progression, metastasis, and treatment response.
• Non-steroidal anti-inflammatory drugs (NSAIDs) show potential in reducing cancer incidence and progression, but their impact on TAM-cancer cell interactions is not fully understood.

Purpose of the Study:

• To investigate the effects of human monocyte-conditioned media (CM) on breast cancer cell proliferation.
• To evaluate the impact of piroxicam and sulindac sulfide on key molecular targets involved in cancer cell survival, proliferation, and inflammation.

Main Methods:

• Utilized qRT-PCR, Western blot, ELISA, and zymography to analyze gene and protein expression levels.
• Assessed the effects of CM and NSAID treatment on MCF-7 and MDA-MB-231 breast cancer cell lines.
• Measured expression of RAS, COX-2, IL-6, IL-1β, PAR-4, BCL-2, BAX, Caspase-3, VEGF-a, PGE2, MMP-2, and MMP-9.

Main Results:

• CM significantly increased breast cancer cell survival by upregulating RAS expression, leading to increased COX-2, PGE2, BCL-2, IL-6, IL-1β, VEGF-A, and MMP-9, while downregulating PAR-4.
• Piroxicam and sulindac sulfide demonstrated time- and concentration-dependent inhibition of stimulated cell growth by suppressing RAS expression.
• NSAID treatment led to downregulation of IL-1β, IL-6, COX-2, and PGE2, activation of apoptosis via PAR-4 and Caspase-3 upregulation, and inhibition of BCL-2, VEGF-A, MMP-2, and MMP-9.

Conclusions:

• Piroxicam and sulindac sulfide effectively suppress inflammation-driven breast cancer progression by targeting RAS signaling.
• RAS and PAR-4 signaling pathways represent promising therapeutic targets for breast cancer treatment.