Targeting RBM39 with Tasisulam enhances TRAIL-induced apoptosis through DR5 upregulation and Bcl-2 downregulation in renal cell carcinoma

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in tumor cells but faces limitations due to resistance mechanisms involving anti-apoptotic regulators such as Bcl-2. This study investigates Tasisulam, a molecular glue degrader, that degrades RNA-binding motif protein 39 (RBM39), as a sensitizer for TRAIL-mediated apoptosis in renal cell carcinoma (RCC). Tasisulam enhances TRAIL-induced apoptosis by activating both extrinsic and intrinsic apoptotic pathways, achieved through upregulation of death receptor 5 (DR5) and downregulation of B-cell lymphoma 2 (Bcl-2). Importantly, Tasisulam selectively sensitizes RCC cells to TRAIL-induced apoptosis without affecting normal cells. RBM39 knockdown mimicked the effects of Tasisulam by upregulating DR5, downregulating Bcl-2, and enhancing TRAIL-induced apoptosis, suggesting RBM39 as a critical regulator of these pathways. To address TRAIL instability in vivo, AaLS/TRAIL nanoparticles were employed in combination with Tasisulam in a Caki-1 xenograft model. This combination significantly reduced tumor volume and weight compared to single treatments, without observed toxicity. These f indings demonstrate that Tasisulam sensitizes RCC cells to TRAIL-induced apoptosis through RBM39-dependent DR5 upregulation and Bcl-2 downregulation. This combination strategy holds significant promise as a potential solution to overcoming TRAIL resistance and advancing more effective treatment outcomes for RCC.