Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma.

Abstract

Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.

• Authors: Maeva Dufies, Annelies Verbiest, Lindsay S Cooley, Papa Diogop Ndiaye, Xingkang He, Nicolas Nottet, Wilfried Souleyreau, Anais Hagege, Stephanie Torrino, Julien Parola, Sandy Giuliano, Delphine Borchiellini, Renaud Schiappa, Baharia Mograbi, Jessica Zucman-Rossi, Karim Bensalah, Alain Ravaud, Patrick Auberger, Andréas Bikfalvi, Emmanuel Chamorey, Nathalie Rioux-Leclercq, Nathalie M Mazure, Benoit Beuselinck, Yihai Cao, Jean Christophe Bernhard, Damien Ambrosetti, Gilles Pagès
• Journal: Communications biology (Commun Biol) Vol. 4 Issue 1 Pg. 166 (02 05 2021) ISSN: 2399-3642 [Electronic] England
• PMID: 33547392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Proto-Oncogene Proteins
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Renal Cell (drug therapy, genetics, pathology)
• Cell Cycle Proteins (genetics, physiology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cohort Studies
• Drug Resistance, Neoplasm (genetics)
• Embryo, Nonmammalian
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Kidney Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Protein Serine-Threonine Kinases (genetics, physiology)
• Proto-Oncogene Proteins (genetics, physiology)
• Up-Regulation (genetics)
• Zebrafish
• Polo-Like Kinase 1