2. Academic Validation
  3. CYT387, a potent IKBKE inhibitor, suppresses human glioblastoma progression by activating the Hippo pathway

CYT387, a potent IKBKE inhibitor, suppresses human glioblastoma progression by activating the Hippo pathway

  • J Transl Med. 2021 Sep 20;19(1):396. doi: 10.1186/s12967-021-03070-3.
Xin Wang  # 1,  Jie Lu  # 2,  Jing Li 3,  Yang Liu 4,  Gaochao Guo 4,  Qiang Huang 5 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China. wangoncologist@126.com.
  • 2 Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Neurosurgery, Jinan, Shandong, China.
  • 3 Department of Nursing, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
  • 4 Department of Neurosurgery, Renmin Hospital of Henan Province, Zhengzhou, Henan, China.
  • 5 Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China. huangqiang@tmu.edu.cn.
  • 6 Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, People's Republic of China. huangqiang@tmu.edu.cn.
  • # Contributed equally.
PMID: 34544426 DOI: 10.1186/s12967-021-03070-3
Abstract

Recent studies have showed that IKBKE is overexpressed in several kinds of cancers and that IKBKE-knockdown inhibits tumor progression. In this article, we first verified that two glioblastoma cell lines, U87-MG and LN-229, were sensitive to CYT387 by measuring the half maximal inhibitory concentration (IC50) with a CCK-8 assay and then demonstrated that CYT387, as a potent IKBKE inhibitor, suppressed glioblastoma cell proliferation, migration and invasion. Additionally, CYT387 induced cell Apoptosis and arrested the cell cycle at the G2/M checkpoint in vitro. Furthermore, we showed that CYT387 did not simply inhibit IKBKE activity but also decreased IKBKE expression at the protein level rather than at the mRNA level. We discovered that CYT387 restrained malignant tumor progression by activating the Hippo pathway in vitro. By coimmunoprecipitation (co-IP), we showed that IKBKE interacted with TEAD2 and YAP1, thus accelerating TEAD2 and YAP1 transport into the nucleus. In subsequent in vivo experiments, we found that CYT387 inhibited subcutaneous nude mouse tumor growth but had little impact on intracranial orthotopic xenografts, probably due to a limited ability to penetrate the blood-brain barrier (BBB). These results suggest that CYT387 has potential as a new antiglioblastoma drug, but an approach to allow passage through the blood-brain barrier (BBB) is needed.

Keywords

CYT387; Glioblastoma; Hippo pathway; IKBKE.

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