What question did this study set out to answer?

The study investigates how CAV2 affects the proliferation of HNSCC cells and their sensitivity to Cetuximab.

April 4, 2026Open Access

CAV2 Modulates Cetuximab Sensitivity in HNSCC via Ubiquitin-Mediated Disruption of the PACT-PKR Axis

Key Points

The study investigates how CAV2 affects the proliferation of HNSCC cells and their sensitivity to Cetuximab.
Screening of prognosis-associated genes using TCGA database.
Assessment of CAV2's role in cell proliferation and apoptosis using CCK-8 and flow cytometry assays.
Mechanistic analysis through co-immunoprecipitation and ubiquitination assays.
Evaluation of CAV2's impact on Cetuximab sensitivity in vitro and in xenograft models.
Higher CAV2 expression correlates with poor prognosis in HNSCC patients (p = 1.33 × 10−13).
CAV2 knockdown reduces cell proliferation and increases apoptosis from 5.1% to 10.8% (p = 0.004).
CAV2 disruption of the PACT-PKR axis via the ubiquitin-proteasome pathway observed.
CAV2 deficiency lowers the IC50 value for Cetuximab by 6-fold, enhancing tumor suppression by 48.41% compared to Cetuximab alone (p < 0.0001).

Abstract

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) often exhibits limited clinical response to targeted therapies, such as Cetuximab. Identifying key drivers of tumor progression and elucidating the factors that modulate therapeutic sensitivity are essential for improving clinical outcomes. In this study, we aimed to investigate the role of CAV2 in HNSCC proliferation and its impact on Cetuximab sensitivity. Methods: Prognosis-associated genes in HNSCC were screened using the The Cancer Genome Atlas (TCGA) database. The functional role of Caveolin-2 (CAV2) in cell proliferation and apoptosis was assessed via Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays. Mechanistic insights were obtained through co-immunoprecipitation, ubiquitination assays, and proteomic analysis. The impact of CAV2 on Cetuximab sensitivity was evaluated both in vitro and in a xenograft mouse model. Results: Clinical analysis of 43 pairs of HNSCC tumor and adjacent normal tissues revealed that elevated CAV2 expression was significantly associated with poor prognosis in HNSCC patients (95%CI: 1.197–1.7518, p = 1.33 × 10−13). In vitro, knockdown of CAV2 suppressed cell proliferation and significantly increased apoptosis rates (from 5.1% to 10.8%, p = 0.004). Mechanistically, CAV2 interacted with the PACT protein and disrupted the PACT-PKR axis via the ubiquitin–proteasome pathway. Notably, CAV2 deficiency synergized with Cetuximab treatment, reducing the the half maximal inhibitory concentration (IC50) value by 6-fold compared with control cells and suppressing tumor growth by 48.41% in xenograft models compared to Cetuximab monotherapy (p < 0.0001). Conclusions: In conclusion, these findings establish CAV2 as a critical regulator of HNSCC progression and Cetuximab sensitivity via post-translational modulation of the PACT–PKR axis. Targeting the CAV2/PACT/PKR axis may therefore represent a promising therapeutic strategy to potentiate the efficacy of EGFR-targeted therapy in patients with HNSCC.

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