5-Hydroxytryptamine activates a 5-HT/c-Myc/SLC6A4 signaling loop in non-small cell lung cancer

Purpose: Psychological stress is a crucial driver of tumorigenesis and Cancer metastasis. The impact of the stress-associated neurotransmitter 5-hydroxytryptamine (5-HT) on tumor progression is poorly understood. We aimed to identify the role of 5-HT in the pathogenesis of non-small cell lung Cancer (NSCLC) and to identify innovative therapeutic strategies.

Methods: The expression of 5-HT and related signaling molecules was assessed by immunohistochemistry and ELISA in tumor tissues from 30 NSCLC patients. The tumorigenic potential and migrative properties of NSCLC A549 cells were examined by colony-formation and Transwell assays. Western blotting and immunofluorescence staining to evaluate protein expression in NSCLC cells and tumor tissues were performed. Patient survival information was downloaded from the Cancer Genome Atlas (TCGA) database to assess the impact of c-Myc/SLC6A4/5-HT signaling on NSCLC development.

Results: Patients with metastatic NSCLC had increased 5-HT expression in NSCLC tissues. In vitro 5-HT pretreatment significantly strengthened the tumorigenic and metastatic potential of A549 cells. Mechanistically, 5-HT promoted the activity of the transcription factor c-Myc in a tribbles pseudokinase 3 (TRIB3)-dependent manner, and c-Myc upregulated the expression of the 5-HT transporter SCL6A4, thereby promoting 5-HT uptake in A549 cells and forming a 5-HT/c-Myc/SLC6A4/5-HT feedback loop. Azaphen dihydrochloride monohydrate-induced suppression of 5-HT uptake decreased the tumorigenic potential and suppressed distant metastasis of NSCLC cells in vivo.

Conclusions: 5-HT signaling is essential for NSCLC development, and 5-HT uptake inhibitors potentially have therapeutic value in the treatment of NSCLC patients.