Han Chae Young, Patten David A, Kim Se Ik, Lim Jung Jin, Chan David W, Siu Michelle K Y, Han Youngjin, Carmona Euridice, Parks Robin J, Lee Cheol, Di Li-Jun, Lu Zhen, Chan Karen K L, Ku Ja-Lok, Macdonald Elizabeth A, Vanderhyden Barbara C, Mes-Masson Anne-Marie, Ngan Hextan Y S, Cheung Annie N Y, Song Yong Sang, Bast Robert C, Harper Mary-Ellen, Tsang Benjamin K
Departments of Obstetrics & Gynecology and Cellular & Molecular Medicine, Centre for Infection, Immunity and Inflammation, Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
Cancers (Basel). 2021 Jul 7;13(14):3399. doi: 10.3390/cancers13143399.
In 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.
在上皮性卵巢癌（EOC）中，卡铂/顺铂诱导的化疗耐药是成功治疗的主要障碍。有氧糖酵解是癌症的一个共同特征。然而，糖酵解代谢在化疗耐药中的作用及其对EOC临床结局的影响尚不清楚。在此，我们展示了关键糖酵解酶己糖激酶II（HKII）与活化的P-p53（Ser15）在生物能量学和化学敏感性调节中的功能相互作用。通过在癌细胞和人EOC肿瘤切片中使用邻近连接评估的转化方法，我们发现化疗后核HKII-P-p53（Ser15）相互作用增加，并作为化疗反应性的决定因素发挥预后生物标志物的作用。我们还证明，p53是EOC中糖酵解控制下细胞内核HKII转运所必需的，与化学敏感性相关。机制上，顺铂诱导的P-p53（Ser15）在化疗敏感的EOC细胞中募集HKII和凋亡诱导因子（AIF），使其从线粒体转运至细胞核，引发AIF诱导的凋亡。相反，在p53缺陷的化疗耐药EOC细胞中，HKII和AIF在线粒体中强烈结合，因此凋亡受到抑制。总体而言，我们的研究结果表明核HKII-P-p53（Ser15）相互作用与化学敏感性有关，并可为铂类治疗期间作为有前景的生物标志物提供有效的临床策略。
