2. Academic Validation
  3. TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC

TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC

  • Cell Death Dis. 2022 May 11;13(5):450. doi: 10.1038/s41419-022-04909-3.
Huimin Sun  # 1 2,  Jianzhong Zheng  # 3 4,  Juanjuan Xiao  # 5 6,  Juntao Yue 7,  Zhiyuan Shi 3 4,  Zuodong Xuan 3 4,  Chen Chen 3 4,  Yue Zhao 3 4,  Wenbin Tang 3 4,  Shaopei Ye 3 4,  Jinxin Li 3 4,  Qiumin Deng 2 3,  Lei Zhang 8,  Feng Zhu 9 10 11,  Chen Shao 12
Affiliations

Affiliations

  • 1 Central Laboratory, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China.
  • 2 The Key Laboratory for Endocrine-Related Cancer precision Medicine of Xiamen, Xiamen, 361102, Fujian, China.
  • 3 School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China.
  • 4 Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China.
  • 5 Cancer Research Institute, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
  • 6 Guangxi Health Commission Key Laboratory of Novel Onco-Kinases in Target Therapy, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
  • 7 Department of Urology, 985th hospital of PLA, Taiyuan, 030002, Shanxi, China.
  • 8 Department of Public healthy, Xiamen University, Xiamen, 361102, Fujian, China.
  • 9 Cancer Research Institute, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
  • 10 Guangxi Health Commission Key Laboratory of Novel Onco-Kinases in Target Therapy, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
  • 11 Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China. [email protected].
  • 12 Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 35546143 DOI: 10.1038/s41419-022-04909-3
Abstract

TOPK/PBK (T-LAK Cell-Originated Protein Kinase) is a serine/threonine kinase that is highly expressed in a variety of human tumors and is associated with poor prognosis in many types of human malignancies. Its activation mechanism is not yet fully understood. A bidirectional signal transduced between TOPK and ERK2 (extracellular signal-regulated kinase 2) has been reported, with ERK2 able to phosphorylate TOPK at the Thr9 residue. However, mutated TOPK at Thr9 cannot repress cellular transformation. In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2. Phospho-TOPK (S32) was found to be involved in the resistance of renal cell carcinoma (RCC) to sorafenib. Herein, combined a TOPK Inhibitor with sorafenib could promoted the Apoptosis of sorafenib-resistant RCC. High expression of HGF/c-met contributes to activation of p-TOPK (S32) during the development of sorafenib resistance in RCC. The current research presents a possible mechanism of sorafenib resistance in RCC and identifies a potential diagnostic marker for predicting sorafenib resistance in RCC, providing a valuable supplement for the clinically targeted treatment of advanced RCC.

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