Bioinformatic Analysis of Tricyclic Antidepressants on Oral Cancer

Objectives: Epidermal growth factor receptor (EGFR) is a key player in pathogenesis of oral cancer. We identified that inhibition of the lysosomal enzyme acid sphingomyelinase (ASM) with fendiline or tricyclic antidepressants (TCAs) results in inhibition of EGFR through depletion of plasma membrane (PM) cholesterol. Like ASM, other endo-lysosomal proteins are required for maintenance of cholesterol on the PM and likely regulate EGFR function. We hypothesized that (1) occurrence of head and neck cancer (HNC) will be less in individuals on TCAs compared to those who are not, and (2) in HNC, expression of EGFR will correlate with expression of genes that encode for endolysosomal proteins involved in cholesterol trafficking.

Methods: Using Allscripts database, occurrence of HNC in a test population of 117,511 adults who were prescribed an antidepressant at least a year prior to cancer diagnosis were compared to age and gender matched control population (117,489) and correlation with age, gender, and tobacco were analyzed. We also examined the correlation between EGFR expression level, mutation status and expression of 115 endo-lysosomal genes using TCGA HNC database.


Results: Analysis of the Allscripts database revealed that 0.08% of the control and 0.27% of the test population had HNC diagnosis. HNC occurrence was higher in individuals on antidepressants, regardless of the class of antidepressant taken. Analysis of TCGA database revealed that of the 115 genes analyzed, expression of 50 genes (including SMPD1 which encodes for ASM) positively correlated with EGFR expression, and expression of 49 negatively correlated, while the others showed no statistically significant correlation.
Conclusions: We were unable to show that the occurrence of HNC is less in individuals taking TCA compared to those who are not. We were able to show expression of 50 endolysosomal genes, positively correlated with EGFR expression, and expression of 49 negatively correlated.