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Updated: May 23, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Targeting RBM39 with Tasisulam enhances TRAIL-induced apoptosis through DR5 upregulation and Bcl-2 downregulation in
Ji Hoon Jang1, Haein Kim2, Heejin Jun2
1Department of Anatomy, College of Medicine, Yeungnam University, 170 Hyeonchung-ro, Nam-Gu, Daegu 42415, Republic of Korea.
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 findings 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.
Insights
Tasisulam, a novel degrader, enhances TRAIL therapy for renal cell carcinoma (RCC) by targeting RBM39. This approach overcomes resistance, selectively killing tumor cells via apoptosis induction without harming normal cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapy
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows selective anti-cancer activity but is limited by resistance.
- Anti-apoptotic proteins like B-cell lymphoma 2 (Bcl-2) contribute to TRAIL resistance in various cancers.
Purpose of the Study:
- To investigate Tasisulam, a molecular glue degrader of RNA-binding motif protein 39 (RBM39), as a sensitizer for TRAIL-mediated apoptosis in renal cell carcinoma (RCC).
- To elucidate the mechanisms by which Tasisulam overcomes TRAIL resistance in RCC.
- To evaluate the in vivo efficacy and safety of Tasisulam combined with TRAIL delivery systems.
Main Methods:
- Tasisulam's effect on apoptosis, death receptor 5 (DR5), and Bcl-2 expression in RCC cells was assessed.
- RNA interference (RNAi) was used to knock down RBM39 to mimic Tasisulam's effects.
- AaLS/TRAIL nanoparticles were combined with Tasisulam in a Caki-1 xenograft mouse model.
Main Results:
- Tasisulam significantly enhanced TRAIL-induced apoptosis in RCC cells by upregulating DR5 and downregulating Bcl-2.
- RBM39 knockdown replicated Tasisulam's effects, confirming RBM39's role in sensitizing cells to TRAIL.
- The combination of Tasisulam and AaLS/TRAIL nanoparticles effectively suppressed tumor growth in vivo with no observed toxicity.
Conclusions:
- Tasisulam sensitizes RCC cells to TRAIL-induced apoptosis through RBM39-dependent modulation of DR5 and Bcl-2.
- This combination therapy offers a promising strategy to overcome TRAIL resistance in RCC.
- Tasisulam represents a potential therapeutic agent for improving treatment outcomes in renal cell carcinoma.
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