Triptolide as a Chemosensitizer in Human Papillomavirus Head and Neck Squamous Cell Carcinoma Through TP53

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally and has demonstrated an etiological shift over recent decades. Human papillomavirus (HPV) infection is a key risk factor for HNSCC, and its incidence has been rising since 1980. HPV-associated HNSCC display a unique tumorigenesis process and respond differently to traditional HNSCC treatment. Triptolide, a natural derivative, has shown promise as a chemosensitizer against HPV-positive HNSCC. The aim of this study was to investigate activity of triptolide in HNSCC in addition to in silico analysis of triptolide gene targets.

Effects of triptolide on proliferation of HPV-positive and HPV-negative HNSCC cells were evaluated using an MTT assay in vitro. Effects of triptolide on TP53 promoter activity and phosphorylation of TP53 protein were measured by reporter gene assay and western blot respectively. Next, enrichment of triptolide gene targets was evaluated through cBioPortal and The Cancer Genome Atlas (TCGA) with a subsequent STRING analysis.

Triptolide acts as a chemosensitizer in combination with low-dose cisplatin. This effect is most pronounced in HPV-positive cells. HPV-positive cells also show increased TP53 promoter activity and TP53 protein phosphorylation. STRING analysis shows involvement of JAK-STAT signaling, interleukin-23 signaling, and apoptosis pathways in HPV-positive samples. In HPV-negative samples, enriched triptolide targets are implicated in RUNX3 regulation of CDKN1A transcription and interleukin-4, interleukin-13, and interleukin-17 signaling.

Triptolide acts as an in vitro chemosensitizer in HPV-positive HNSCC, likely through reactivation of wild-type TP53 and restoration of apoptotic control. Inflammatory cytokine signaling blockade may provide an additional mechanism contributing to this chemosensitizing effect.