Abstract 3709: The interplay between Aldehyde dehydrogenase 1 and TGF-β in therapeutic resistant glioblastoma
Authors: Chan-Chuan Liu, Meng-Xuan Lin, I-Chun Yeh, Chun-I Sze
Journal: Cancer Research (2019)

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor. In spite of aggressive treatment, easily developing resistance results in GBM recurrence and poor prognosis. TGF-β is a well-known molecule which induces epithelial-to-mesenchymal transition and participates in cancer resistance. Aldehyde dehydrogenase 1 (ALDH1) is a new cancer stem cell marker. How ALDH1 contributes to GBM resistance remains poorly understood. Therefore, we hypothesized that the interplay between ALDH1 and TGF-β may play a role in GBM resistance. We mimicked clinical standard GBM treatment procedure, which utilizes consecutive radiation and temozolomide (TMZ), and selected the median effective dose of radiation and the TMZ dose of growth inhibition of 50% to develop three therapeutic-resistant models by using U87MG and 1306MG cell lines. It included resistance against radiation, TMZ, and radiation plus TMZ. To develop radiation resistance, U87MG required 2 Gy irradiation for four times while 1306MG required 3.5 Gy irradiation for six times. On the other hand, to establish TMZ resistance, U87MG required TMZ treatment for three times while 1306MG required TMZ treatment twice. U87MG is a low-ALDH1 expression cell line, in contrast, 1306MG is high-ALDH1 expression cell line. They showed differential responses to radiation and TMZ. Interestingly, while GBM developed TMZ resistance, U87MG increased ALDH1 expression, however, 1306MG reduced ALDH1 expression. These cell lines elevated TGF-β secretion as they developed resistance against radiation (995.4 pg/ml vs. 1234.1 pg/ml in U87MG; 25.7 pg/ml vs. 1607.7 pg/ml in 1306MG) and radiation plus TMZ (995.4 pg/ml vs. 1058.1 pg/ml in U87MG; 25.7 pg/ml vs. 1207.0 pg/ml in 1306MG). Also, therapeutic-resistant GBM accelerated cell proliferation, enhanced cell motility, and displayed TGF-β-induced mesenchymal differentiation by up-regulating N-cadherin and fibronectin. Developing resistance increased ALDH1 expression. Disulfiram (DSF) is a drug which is able to inhibit ALDH activity. We found that inhibiting ALDH1 by DSF sensitized GBM to TMZ in both parental and TMZ-resistant GBM. Moreover, DSF or ALDH1 activity specific inhibitor NCT-501 reduced cell mobility, reversed mesenchymal differentiation via down-regulating N-cadherin and fibronectin, and decreased CD133 expression. Combined DSF and TGF-β receptor inhibitor exaggerated cytotoxicity and enhanced cell mobility inhibition in radiation resistant 1306MG and radiation plus TMZ resistant U87MG. Therefore, the differential expression of ALDH1 may influence the sensitivity of treatment and response to TGF-β inhibitor. Accordingly, ALDH1 may contribute to GBM resistance via modulating TGF-β signaling. Targeting ALDH1 and TGF-β receptor may improve the efficacy of GBM therapy. Citation Format: Chan-Chuan Liu, Meng-Xuan Lin, I-Chun Yeh, Chun-I Sze. The interplay between Aldehyde dehydrogenase 1 and TGF-β in therapeutic resistant glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3709.