2. Academic Validation
  3. Role of endoplasmic reticulum stress in apoptosis induced by HK2 inhibitor and its potential as a new drug combination strategy

Role of endoplasmic reticulum stress in apoptosis induced by HK2 inhibitor and its potential as a new drug combination strategy

  • Cell Stress Chaperones. 2022 May;27(3):273-283. doi: 10.1007/s12192-022-01267-z.
Jiateng Zhong  # 1 2,  Shuya Lu  # 3,  Xiaoling Jia 3,  Qian Li 3,  Lei Liu 3,  Pei Xie 4,  Guodong Wang 5,  Manman Lu 3,  Wuji Gao 3,  Tiesuo Zhao 6 7,  Qianqing Wang 4,  Wei Su 8,  Na Li 9
Affiliations

Affiliations

  • 1 Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. jtzhong@xxmu.edu.cn.
  • 2 Department of Gynecology, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, Henan, China. jtzhong@xxmu.edu.cn.
  • 3 Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
  • 4 Department of Gynecology, The Fourth Clinical College of Xinxiang Medical University, Xinxiang, Henan, China.
  • 5 Nursing School, Xinxiang Medical University, Xinxiang, China.
  • 6 Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
  • 7 Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, Henan, China.
  • 8 Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. hnswei@163.com.
  • 9 Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China. Lina@xxmu.edu.cn.
  • # Contributed equally.
PMID: 35355227 DOI: 10.1007/s12192-022-01267-z
Abstract

Compared with normal cells, tumor cells mainly obtain energy through aerobic glycolysis. Hexokinase 2 (HK2) plays a key role in the regulation of tumor cell aerobic glycolysis, and targeting HK2 has become a new strategy for Cancer treatment. However, little is known about the role of HK2 in colon Cancer and the regulation of its targeted inhibitors. In this study, we found that the expression of HK2 in colorectal Cancer tissues was significantly higher than that in adjacent tissues, and the expression level of HK2 in metastatic colorectal Cancer was further increased. Meanwhile, the expression level of HK2 was closely related to clinical TNM stage and outcome of colorectal Cancer patients. We provide here evidence that HK2 inhibitor 3-Bromopyruvate acid (3-BP) can significantly inhibit the survival and proliferation of colon Cancer cells, and induce Apoptosis through mitochondrial Apoptosis signaling pathway. In addition, we found that 3-BP can also induce endoplasmic reticulum stress in colon Cancer cells, the mechanism may be through the increase of intracellular calcium concentration. In vitro and in vivo experiments showed that inhibition of endoplasmic reticulum stress could further increase the proliferation inhibition and Apoptosis induced by 3-BP. Collectively, our results show that HK2 is highly expressed in colorectal Cancer. 3-BP, an inhibitor of HK2, can induce Apoptosis and endoplasmic reticulum stress in colon Cancer cells. Endoplasmic reticulum stress plays a protective role in cell death induced by 3-BP. This result suggested that targeting HK2 and endoplasmic reticulum stress may be a valuable strategy in targeted and combination therapy of colon Cancer.

Keywords

3-Bromopyruvate acid; Colon cancer; Endoplasmic reticulum stress; Hexokinase 2·apoptosis.

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