Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance

Yu-Ling Tsai; Hsin-Han Chang; Ying-Chuan Chen; Yu-Chan Chang; Ying Chen; Wen-Chiuan Tsai

doi:10.3390/biomedicines8090339

Molecular Mechanisms of KDELC2 on Glioblastoma Tumorigenesis and Temozolomide Resistance

Biomedicines. 2020 Sep 10;8(9):339. doi: 10.3390/biomedicines8090339.

Authors

Yu-Ling Tsai¹, Hsin-Han Chang^{2

3}, Ying-Chuan Chen⁴, Yu-Chan Chang⁵, Ying Chen³, Wen-Chiuan Tsai^{1

6}

Affiliations

¹ Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
² Graduate Institute of Life Science, National Defense Medical Center, Taipei 114, Taiwan.
³ Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan.
⁴ Department of Physiology and Biophysics, National Defense Medical Center, Taipei 114, Taiwan.
⁵ Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 115, Taiwan.
⁶ Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 114, Taiwan.

Abstract

The activation of the Notch pathway induces glioblastoma (GBM) development. Since KDEL (Lys-Asp-Glu-Leu) containing 2 (KDELC2) is involved in the Notch pathway, the detailed mechanism is still undetermined. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases revealed that KDELC2 mRNA was associated with oncologic factors of GBM. U87, LN229, LNZ308, U118MG, and GBM8401 cells showed higher KDELC2 expression than normal brain tissues. The results of MTT, wound healing, and invasion assays proved that KDELC2 knockdown suppressed GBM-aggressive behaviors. The inhibitory properties of GBM stemness and angiogenesis under KDELC2 knockdown were evaluated by tumor spheroid and tube formation assays. Suppression of KDELC2 downregulated Notch factors' expressions, including KDELC1, pofut1, Notch receptors 1-3, and HES-1. Immunoblot assay showed that KDELC2 knockdown promoted tumor apoptosis by downregulating PI3k/mTOR/Akt, MAPK/ERK, and NF-kB pathways. The combination of KDELC2 knockdown and temozolomide (TMZ) treatment had an optimal therapeutic effect by suppressing MGMT expression. Results of an orthotopic xenograft animal model and human tissue confirmed that KDELC2 correlated with glioma proliferation, advanced grades, and poor prognosis. Therefore, KDELC2 might be a potential pharmacological target to inhibit tumorigenesis, epithelial-mesenchymal transition, angiogenesis, and chemo-resistance of GBM.

Keywords: KDELC2; Notch; glioblastoma; temozolomide.