BCL2L13 Influences Autophagy and Ceramide Metabolism without Affecting Temozolomide Resistance in Glioblastoma

Courtney Clark, Amir Barzegar Behrooz, Simone C Da Silva Rosa, Jaodi Jacobs, Xiaohui Weng, Abhay Srivastava, Rui Vitorino, Sudharsan Rao Ande, Amir Ravandi, Sanjiv Dhingra, Stevan Pecic, Donald Miller, Shahla Shojaei, Saeid Ghavami
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Abstract

Temozolomide (TMZ) resistance in glioblastoma (GB) poses a significant therapeutic challenge. We developed a TMZ-resistant (TMZ-R) U251 GB model, revealing distinct differences in cell viability, apoptosis, autophagy, and lipid metabolism between TMZ-R and non-resistant (TMZ-NR) cells. TMZ-NR cells exhibited heightened sensitivity to TMZ-induced apoptosis, while TMZ-R cells-maintained viability. Autophagy flux was completely inhibited in TMZ-R cells, indicated by LC3βII and SQSTM1 accumulation. BCL2L13, which showed higher expression in TMZ-R cells, demonstrated increased interaction with Ceramide Synthase 6 (CerS6) and reduced interaction with Ceramide Synthase 2 (CerS2) in TMZ-NR cells. BCL2L13 knockdown (KD) disrupted autophagy flux, decreasing autophagosome accumulation in TMZ-R cells while increasing it in TMZ-NR cells. These changes contributed to altered ceramide profiles, where TMZ-R cells displayed elevated levels of Cer 16:0, 18:0, 20:0, 22:0, 24:0, and 24:1. Our findings highlight BCL2L13 and altered ceramide metabolism as potential therapeutic targets to overcome TMZ resistance in GB.
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BCL2L13影响自噬和神经酰胺代谢,但不影响胶质母细胞瘤对替莫唑胺的耐药性
胶质母细胞瘤(GB)中的替莫唑胺(TMZ)耐药性是一项重大的治疗挑战。我们开发了一种TMZ耐药(TMZ-R)U251 GB模型,揭示了TMZ-R和非耐药(TMZ-NR)细胞在细胞活力、凋亡、自噬和脂质代谢方面的明显差异。TMZ-NR细胞对TMZ诱导的细胞凋亡表现出更高的敏感性,而TMZ-R细胞则保持活力。自噬通量在 TMZ-R 细胞中被完全抑制,表现为 LC3βII 和 SQSTM1 的积累。BCL2L13在TMZ-R细胞中表达较高,在TMZ-NR细胞中与神经酰胺合成酶6(CerS6)的相互作用增强,而与神经酰胺合成酶2(CerS2)的相互作用减弱。BCL2L13基因敲除(KD)扰乱了自噬通量,在TMZ-R细胞中减少了自噬体的积累,而在TMZ-NR细胞中则增加了自噬体的积累。这些变化导致了神经酰胺谱的改变,TMZ-R 细胞中的神经酰胺 16:0、18:0、20:0、22:0、24:0 和 24:1 水平升高。我们的研究结果突显了 BCL2L13 和神经酰胺代谢的改变是克服 GB 中 TMZ 耐药性的潜在治疗靶点。
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