PLK1 and FoxM1 expressions positively correlate in papillary thyroid carcinoma and their combined inhibition results in synergistic anti-tumor effects

Polo-like kinase 1 (PLK1; also known as serine/threonine-protein kinase PLK1) serves as a central player in cell proliferation, exerting critical regulatory roles in mitotic processes and cell survival. We conducted an analysis of PLK1 protein expression in a large cohort of samples from papillary thyroid carcinoma (PTC) patients and examined its functional significance in PTC cell lines, both in vitro and in vivo. PLK1 overexpression was noted in 54.2% of all PTC and was significantly associated with aggressive clinicopathological parameters; it was also found to be an independent prognostic marker for shorter recurrence-free survival. Given the significant association between PLK1 and forkhead box protein M1 (FoxM1), and their concomitant overexpression in a large proportion of PTC samples, we explored their correlation and their combined inhibitions in PTC in vitro and in vivo. Inhibition of PLK1 expression indeed suppressed cell proliferation, leading to cell cycle arrest and apoptosis in PTC cell lines. Significantly, the downregulation of PLK1 reduced the self-renewal capability of spheroids formed from PTC cells. Immunoprecipitation analysis shows that PLK1 binds to FoxM1 and vice versa in vitro. Mechanistically, PLK1 knockdown suppresses FoxM1 expression, whereas inhibition of FoxM1 does not affect PLK1 expression, which suggests that PLK1 acts through the FoxM1 pathway. The combined treatment of a PLK1 inhibitor (volasertib) and a FoxM1 inhibitor (thiostrepton) demonstrated a synergistic effect in reducing PTC cell growth in vitro and delaying tumor growth in vivo. This study highlights the important role of PLK1 in PTC tumorigenesis and prognosis. It also highlights the synergistic therapeutic potential of dual-targeting PLK1 and FoxM1 in PTC, unveiling a potential innovative therapeutic strategy for managing aggressive forms of PTC.