TROP-2 Promotes Cell Proliferation via the AKT-Mediated PKCα Pathway and Is a Novel Target for Antibody-Drug Conjugates in Penile Carcinoma.

BACKGROUND: Current chemotherapy treatments, including the TIP (Taxol, Ifosfamide, Cisplatin) regimen, have shown limited effects but strong side effects in advanced Penile squamous cell carcinoma (PSCC) patients. Trophoblast cell-surface antigen-2 (TROP-2) is a novel target for antibody-drug conjugate (ADC) drugs and has been proven to be effective in several human cancers. This study aimed to explore the biological function and potential of the ADC target in PSCC cells. METHODS: A total of 196 PSCC tumor tissue specimens and clinicopathological data were collected. TROP-2 expression was detected by IHC, and the correlation between TROP-2 expression and the clinicopathological data of patients was analysed through statistical methods. Then, a series of in vivo and in vitro experiments were conducted to investigate the mechanism by which TROP-2 promotes PSCC cell proliferation. Additionally, the efficacy of TROP-2-targeted ADC and cisplatin was tested in PSCC cell lines and animal models. RESULTS: Immunohistochemistry (IHC) revealed that TROP-2 was highly expressed in 60.2% of tumor specimens, and statistical analysis revealed that high TROP-2 expression correlated with advanced pT and pN stages and extranodal extension (ENE), as well as poor prognosis. Knockdown of TROP-2 inhibited the proliferation of PSCC cells both in vivo and in vitro, and this inhibitory effect was later proven to be mediated by protein kinase B (AKT), which is involved in the protein kinase C alpha (PKCα) signalling pathway. Furthermore, compared with cisplatin, TROP-2 targeted ADC could achieve an equivalent inhibitory effect on the proliferation of PSCC both in vivo and in vitro. CONCLUSION: TROP-2 promoted PSCC cell proliferation via AKT/PKCα-dependent pathway, and TROP-2-targeted ADC-drug has a gratifying inhibitory effect on PSCC proliferation both in vivo and in vitro.