Protein kinase C zeta promotes thyroid Cancer progression and represents a novel therapeutic target: evidence from specific atypical PKC inhibitor 2-acetyl-1,3-cyclopentanedione inhibitor studies.

BACKGROUND: Poorly differentiated and anaplastic thyroid carcinomas represent aggressive malignancies with limited therapeutic options and poor prognosis. Protein kinase C zeta (PKCζ), an atypical PKC isozyme, has emerged as a critical regulator in various cancers, but its role in thyroid cancer progression remains largely unexplored. This study investigated PKCζ expression patterns in thyroid cancer and evaluated its therapeutic potential using the specific atypical PKC inhibitor 2-acetyl-1,3-cyclopentanedione (ACPD). METHODS: PKCζ expression and phosphorylation were analyzed in thyroid tissue samples from 20 patients and multiple thyroid cancer cell lines using Western blot analysis. Functional studies employed PKCζ overexpression, knockdown, and ACPD treatment in BCPAP (papillary) and 8505C (poorly differentiated) cell lines. Cell proliferation, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) markers were assessed. Therapeutic efficacy was evaluated in xenograft mouse models with ACPD treatment. RESULTS: PKCζ expression and phosphorylation progressively increased from normal thyroid tissue through papillary, poorly differentiated, to anaplastic thyroid carcinomas. ACPD treatment (5 μM) significantly suppressed malignant phenotypes in 8505C cells, including reduced proliferation, colony formation, migration, and invasion, while reversing EMT marker expression. PKCζ knockdown reproduced these anti-tumorigenic effects, confirming specificity. PKCζ overexpression in BCPAP cells enhanced malignant behaviors, which were effectively counteracted by ACPD treatment. In vivo studies demonstrated that ACPD treatment significantly reduced tumor growth in both cell line-derived xenograft models. CONCLUSION: PKCζ activation correlates with thyroid cancer aggressiveness and drives malignant progression through EMT regulation. ACPD effectively targets PKCζ-mediated oncogenic pathways, suggesting PKCζ inhibition as a promising therapeutic strategy for aggressive thyroid cancers.