TXN promotes tumorigenesis by activating the ERK1/2 and ERK5 signaling pathways regulating c-Myc in non-small cell lung cancer.

Abstract

Lung cancer is the primary cause of cancer-related deaths worldwide, particularly for non-small cell lung cancer (NSCLC). However, the exact mechanism underlying tumor formation remains unclear. It is widely acknowledged that inflammation and oxidative stress occur in the tumor microenvironment, promoting cell malignant growth and metastasis. Thioredoxin-1 (TXN), the main regulator of oxidative stress, plays a significant role in the development of NSCLC. However, the specific tumor-promoting mechanism is still being investigated. This study aimed to examine the function and mechanism of TXN in NSCLC. The effects of knockdown or overexpression TXN on cell proliferation, invasion and apoptosis were evaluated by Cell Counting Kit-8, colony formation, wound healing, transwell, TUNEL staining, and flow cytometric assays. Western blotting was performed to analyze the regulation of TXN and downstream proteins suppressed by genes and pharmacology. TXN knockdown significantly suppressed cell proliferation, invasion and promoted apoptosis both in vitro and in vivo, whereas TXN overexpression reversed these malignant phenotypes. We found that TXN regulated c-Myc expression through ERK1/2 and ERK5 signaling pathways. Suppressing ERK1/2 led to the compensatory activation of ERK5, and simultaneously inhibiting ERK1/2 and ERK5 synergistically reduced c-Myc expression, further attenuating cell proliferation, invasion and enhanced apoptosis. Our results indicated tumor promotion of TXN in NSCLC and TXN regulated c-Myc in the interest of tumorigenesis through ERK1/2 and ERK5 signaling pathways. Targeting TXN and blocking the ERK1/2 and ERK5 pathways could potentially offer new therapeutic strategies for NSCLC.