Nuclear HKII-P-p53 (Ser15) Interaction is a Prognostic Biomarker for Chemoresponsiveness and Glycolytic Regulation in Epithelial Ovarian Cancer.
Chae Young Han, David A Patten, Se Ik Kim, Jung Jin Lim, David W Chan, Michelle K Y Siu, Youngjin Han, Euridice Carmona, Robin J Parks, Cheol Lee, Li-Jun Di, Zhen Lu, Karen K L Chan, Ja-Lok Ku, Elizabeth A Macdonald, Barbara C Vanderhyden, Anne-Marie Mes-Masson, Hextan Y S Ngan, Annie N Y Cheung, Yong Sang Song, Robert C Bast, Mary-Ellen Harper, Benjamin K Tsang
Cancers 2021 Jul 07In epithelial ovarian cancer (EOC), carboplatin/cisplatin-induced chemoresistance is a major hurdle to successful treatment. Aerobic glycolysis is a common characteristic of cancer. However, the role of glycolytic metabolism in chemoresistance and its impact on clinical outcomes in EOC are not clear. Here, we show a functional interaction between the key glycolytic enzyme hexokinase II (HKII) and activated P-p53 (Ser15) in the regulation of bioenergetics and chemosensitivity. Using translational approaches with proximity ligation assessment in cancer cells and human EOC tumor sections, we showed that nuclear HKII-P-p53 (Ser15) interaction is increased after chemotherapy, and functions as a determinant of chemoresponsiveness as a prognostic biomarker. We also demonstrated that p53 is required for the intracellular nuclear HKII trafficking in the control of glycolysis in EOC, associated with chemosensitivity. Mechanistically, cisplatin-induced P-p53 (Ser15) recruits HKII and apoptosis-inducing factor (AIF) in chemosensitive EOC cells, enabling their translocation from the mitochondria to the nucleus, eliciting AIF-induced apoptosis. Conversely, in p53-defective chemoresistant EOC cells, HKII and AIF are strongly bound in the mitochondria and, therefore, apoptosis is suppressed. Collectively, our findings implicate nuclear HKII-P-p53(Ser15) interaction in chemosensitivity and could provide an effective clinical strategy as a promising biomarker during platinum-based therapy.
Citation
Chae Young Han, David A Patten, Se Ik Kim, Jung Jin Lim, David W Chan, Michelle K Y Siu, Youngjin Han, Euridice Carmona, Robin J Parks, Cheol Lee, Li-Jun Di, Zhen Lu, Karen K L Chan, Ja-Lok Ku, Elizabeth A Macdonald, Barbara C Vanderhyden, Anne-Marie Mes-Masson, Hextan Y S Ngan, Annie N Y Cheung, Yong Sang Song, Robert C Bast, Mary-Ellen Harper, Benjamin K Tsang. Nuclear HKII-P-p53 (Ser15) Interaction is a Prognostic Biomarker for Chemoresponsiveness and Glycolytic Regulation in Epithelial Ovarian Cancer. Cancers. 2021 Jul 07;13(14)
PMID: 34298618
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