2. Academic Validation
  3. Targeting the molecular chaperone CCT2 inhibits GBM progression by influencing KRAS stability

Targeting the molecular chaperone CCT2 inhibits GBM progression by influencing KRAS stability

  • Cancer Lett. 2024 May 28:590:216844. doi: 10.1016/j.canlet.2024.216844.
Feihu Zhao 1,  Zhong Yao 2,  Yaquan Li 1,  Wenbo Zhao 1,  Yanfei Sun 1,  Xiaobing Yang 1,  Zhimin Zhao 1,  Bin Huang 1,  Jian Wang 3,  Xingang Li 4,  Anjing Chen 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, PR China; Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250017, PR China.
  • 2 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, PR China.
  • 3 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, PR China; Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250017, PR China; Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway.
  • 4 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, PR China; Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250017, PR China. Electronic address: lixg@sdu.edu.cn.
  • 5 Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, 250012, PR China; Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250017, PR China. Electronic address: chenaj@sdu.edu.cn.
PMID: 38582394 DOI: 10.1016/j.canlet.2024.216844
Abstract

Proper protein folding relies on the assistance of molecular chaperones post-translation. Dysfunctions in chaperones can cause diseases associated with protein misfolding, including Cancer. While previous studies have identified CCT2 as a chaperone subunit and an Autophagy receptor, its specific involvement in glioblastoma remains unknown. Here, we identified CCT2 promote glioblastoma progression. Using approaches of coimmunoprecipitation, mass spectrometry and surface plasmon resonance, we found CCT2 directly bound to KRAS leading to increased stability and upregulated downstream signaling of KRAS. Interestingly, we found that dihydroartemisinin, a derivative of artemisinin, exhibited therapeutic effects in a glioblastoma animal model. We further demonstrated direct binding between dihydroartemisinin and CCT2. Treatment with dihydroartemisinin resulted in decreased KRAS expression and downstream signaling. Highlighting the significance of CCT2, CCT2 overexpression rescued the inhibitory effect of dihydroartemisinin on glioblastoma. In conclusion, the study demonstrates that CCT2 promotes glioblastoma progression by directly binding to and enhancing the stability of the KRAS protein. Additionally, dihydroartemisinin inhibits glioblastoma by targeting the CCT2 and the following KRAS signaling. Our findings overcome the challenge posed by the undruggable nature of KRAS and offer potential therapeutic strategies for glioblastoma treatment.

Keywords

CCT2; Dihydroartemisinin; GBM; KRAS.

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