Cyclooxygenase-2 expression induced by photofrin photodynamic therapy involves the p38 MAPK pathway

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Photodynamic therapy (PDT) with Photofrin (PH) treats solid tumors by inducing oxidative stress.
• PDT also upregulates pro-survival molecules like cyclooxygenase-2 (COX-2), a target for combination therapy.
• Understanding the signaling pathways of PH-PDT-induced COX-2 is crucial for improving treatment efficacy.

Purpose of the Study:

• To investigate the molecular mechanisms underlying PH-PDT-mediated COX-2 expression.
• To identify key signaling pathways and transcription factors involved in COX-2 induction by PH-PDT.
• To evaluate the potential of targeting these pathways for enhanced cancer therapy.

Main Methods:

• Utilized COX-2 promoter reporter constructs with mutated transcription elements (NFkappaB, CRE-2, C/EBP, AP-1).
• Performed transcription factor binding assays to assess nuclear protein interactions.
• Examined kinase phosphorylation (SAPK/JNK, p38 MAPK, ERK1/2) and utilized specific pathway inhibitors (SP600125, SB203580, SB202190, PD98059, U0126, SN50).

Main Results:

• PH-PDT activated NFkappaB, CRE-2, c-fos, and c-jun binding.
• p38 MAPK and CRE-2 binding were identified as key mediators of PH-PDT-induced COX-2 expression.
• Inhibitors of p38 MAPK significantly reduced COX-2 mRNA and protein levels.
• SAPK/JNK and ERK1/2 pathways were less critical for COX-2 induction in this model.

Conclusions:

• PH-PDT-induced COX-2 expression involves multiple signaling cascades activated by oxidative stress.
• The p38 MAPK signaling pathway and CRE-2 binding play a significant role in this process.
• Targeting the p38 MAPK pathway presents a potential strategy to enhance the efficacy of PH-PDT in cancer treatment.