Fig. 7. Lercanidipine inhibits glioma progression.

a Lercanidipine specifically inhibits GSC cell viability, compared to NHNP and NHA cells. b, c Membrane tethered form of CD133 were reduced by lercanidipine (7 μM) treatment. c Quantification data for b. d IB detecting CD133, β-catenin and GLT8D1 expressions after lercanidipine (7 μM) treatment. e β-catenin proteins were examined in cytoplasm (C) and nuclear fractions (N) of indicated cells following 7 μM lercanidipine treatment by IB. f, g Tumor spheres derived from indicated GSC cell lines were significantly inhibited following lercanidipine treatment. g Quantification data for f. Scale bar: 500 μm. h Lercanidipine alone or synergizes with TMZ to induce cellular apoptosis. Lercanidipine (7 μM), TMZ (200 μM). i Patient-derived xenograft tumors treated with 5 mg kg⁻¹ lercanidipine via tail vein injection twice every week for four weeks. Indicated xenograft tumors were harvested, tumor weights and volumes were plotted. j GSC11 cells were implanted intracranially into NOD-SCID mice. Mice were treated with vehicle (PBS) or 5 mg kg⁻¹ lercanidipine by tail vein injection daily for 7 days, and the relative survival curves were plotted (n = 5, Kaplan–Meier model with log-rank test). k Representative images of H&E staining for tumor formation of indicated treatments. Scale bar: 2 mm. l Proposed mechanism of GLT8D1 in GSC during glioma progression. Under normoxia condition, low expression of GLT8D1 results in less efficient glycosylation modification in CD133, leading to CD133 degradation through endosomal-lysosomal pathway. On the contrary, GLT8D1 transcripts and proteins are increased under hypoxic conditions in a HIF-1α dependent manner. Therefore, abundant GLT8D1 proteins physically interact with CD133 to promote high glycosylation and stabilization of CD133, which activates Wnt signaling in GSC leading to glioma progression. However, the FECD133 peptide and lercanidipine can inhibit GSC maintenance and tumor growth by blocking GLT8D1-CD133 complex formation or GTL8D1 expression, respectively. Means ± SEM, *P < 0.05,**P < 0.01, ***P < 0.001, t-test.