Abstract 3177: KITENIN leads to resistance against temozolomide through enhancement of cancer stemness factors in mouse glioma model

Abstract

Abstract Background: Recently, a new research spotlighted the role of KITENIN (KAI1 COOH-terminal interacting tetraspanin) on glioma invasiveness and progression, associated with the up-regulation of EMT (epithelial-mesenchymal transition) and cancer stemness markers. In this study, furthermore, it is investigated whether KITENIN leads to resistance against TMZ through enhancement of cancer stemness factors using mouse glioma model. Materials and Methods: TMZ-resistant T98G cell line (T98G/TR) was developed. EMT and cancer stemness markers and KITENIN expression were assessed by Western blotting and qRT-PCR. With KITENIN modulated U251 (knockdown) and GL261 (overexpression) cells, cell viability and apoptotic cell death factors after TMZ treatment were evaluated. Biological role of KITENIN on TMZ-resistance was investigated using magnetic resonance imaging (MRI) and immunofluorescence analysis for tumor sections of orthotopic glioma model. Using human glioma samples and primary cells, the mechanistic link between KITENIN and cancer stemness factors was confirmed. Results: T98G/TR cells showed increased expression of the KITENIN and EMT and cancer stemness factors. Also, In vitro assays revealed that KITENIN knockdown inhibited cell viability against TMZ treatment, whereas KITENIN overexpression promoted their viability, via apoptotic cell death pathway. In orthotopic glioma models, mice implanted with KITENIN-overexpressed cells showed resistance to TMZ on MRI and histopathological examination. The expression of KITENIN/ALDH1 or KITENIN/CD44 were co-localized and significantly higher in tumor sections of mouse transplanted with KITENIN-overexpressed cells than in tumor sections of mouse transplanted with control cells. Genetic down-regulation of KITENIN for KITENIN-overexpressed cell line and primary glioma cells led decreased expression of ALDH1 and CD44. In human glioma samples, high expression of KITENIN was closely related with high expression of ALDH1. Conclusion: KITENIN affects TMZ-resistance in malignant gliomas through induction of ALDH1 and CD44. Therefore, it could be suggested that KITENIN is therapeutic target to overcome TMZ-resistance of malignant gliomas. Citation Format: Kyung-Hwa Lee, Eun-Jung Ahn, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Kyung-Sub Moon. KITENIN leads to resistance against temozolomide through enhancement of cancer stemness factors in mouse glioma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3177. doi:10.1158/1538-7445.AM2017-3177