Mutant p53 Regulates TNFSF10 in Cancer
DOI:
https://doi.org/10.58445/rars.3411Keywords:
p53 mutation, Tumor suppressor protein, TNFSF10Abstract
Tumor suppressor protein p53 is an essential regulator of cell death. p53 activates genes that cause programmed cell death, or apoptosis, which stops damaged cells from dividing and suppresses cancer initiation and progression. About half of all human cancers carry p53 mutations, which affect the protein's normal function and can promote tumor growth. This study investigates the effects ofp53 mutation on the expression of TNFSF10, encoding the pro-apoptotic protein TRAIL. An analysis of transcriptomic data from the DepMap database showed that TNFSF10 is overexpressed in renal cell carcinoma (RCC) cell lines carrying mutant but not wild type p53. The function of TRAIL in promoting the survival of cancer cells was investigated through a literature review. Finally, analysis of drug sensitivity data from the Cancer Therapeutic Response Portal revealed that RCC cells with high expression of TRAIL show increased sensitivity to the bioactivated compound SNS-032. These data suggest that SNS-032 could be used as a treatment to selectively target mutant p53 RCC tumors characterized by high TRAIL expression.
References
Differentiation, 25(1), 104–113. https://doi.org/10.1038/cdd.2017.169
Brown, G. (2021). Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells. International Journal of Molecular Sciences, 22(18), 9667. https://doi.org/10.3390/ijms22189667
Brown, J. S., Amend, S. R., Austin, R. H., Gatenby, R. A., Hammarlund, E. U., & Pienta, K. J. (2023). Updating the Definition of Cancer. Molecular Cancer Research, 21(11), 1142–1147. https://doi.org/10.1158/1541-7786.MCR-23-0411
Conroy, A., Stockett, D. E., Walker, D., Arkin, M. R., Hoch, U., Fox, J. A., & Hawtin, R. E. (2009). SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples. Cancer Chemotherapy and Pharmacology, 64(4), 723–732. https://doi.org/10.1007/s00280-008-0921-5
Elmore, S. (2007). Apoptosis: A Review of Programmed Cell Death. Toxicologic Pathology, 35(4), 495–516. https://doi.org/10.1080/01926230701320337
Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A., & Fares, Y. (2020). Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduction and Targeted Therapy, 5, 28. https://doi.org/10.1038/s41392-020-0134-x
Guerrache, A., & Micheau, O. (2024). TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling. Cells, 13(6), 521. https://doi.org/10.3390/cells13060521
Hsieh, J. J., Purdue, M. P., Signoretti, S., Swanton, C., Albiges, L., Schmidinger, M., Heng, D. Y., Larkin, J., & Ficarra, V. (2017). Renal cell carcinoma. Nature Reviews Disease Primers, 3(1). https://doi.org/10.1038/nrdp.2017.9
Isono, T., Chano, T., Yoshida, T., Kageyama, S., Kawauchi, A., Yonese, J., & Yuasa, T. (2018). Abundance of TRAIL attenuated by HIF2α and c-FLIP affects malignancy in renal cell carcinomas. Oncotarget, 9(33), 23091–23101. https://doi.org/10.18632/oncotarget.25214
Kuribayashi, K., Krigsfeld, G., Wang, W., Xu, Ji., Mayes, P. A., Dicker, D. T., Wu, G. S., & El-Deiry, W. S. (2008). TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell death. Cancer Biology & Therapy, 7(12), 2034–2038. https://doi.org/10.4161/cbt.7.12.7460
Liu, Y., Su, Z., Tavana, O., & Gu, W. (2024). Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell, 42(6), 946–967. https://doi.org/10.1016/j.ccell.2024.04.009
Mustafa, M., Ahmad, R., Tantry, I. Q., Ahmad, W., Siddiqui, S., Alam, M., Abbas, K., Moinuddin, Hassan, Md. I., Habib, S., & Islam, S. (2024). Apoptosis: A Comprehensive Overview of Signaling Pathways, Morphological Changes, and Physiological Significance and Therapeutic Implications. Cells, 13(22), 1838. https://doi.org/10.3390/cells13221838
Ozaki, T., & Nakagawara, A. (2011). Role of p53 in Cell Death and Human Cancers. Cancers, 3(1), 994–1013. https://doi.org/10.3390/cancers3010994
Padala, S. A., Barsouk, A., Thandra, K. C., Saginala, K., Mohammed, A., Vakiti, A., Rawla, P., & Barsouk, A. (2020). Epidemiology of Renal Cell Carcinoma. World Journal of Oncology, 11(3), 79–87. https://doi.org/10.14740/wjon1279
Pimentel, J. M., Zhou, J.-Y., & Wu, G. S. (2023). The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer. Cancers, 15(10), 2752. https://doi.org/10.3390/cancers15102752
Sammons, M. A., Nguyen, T.-A. T., McDade, S. S., & Fischer, M. (2020). Tumor suppressor p53: From engaging DNA to target gene regulation. Nucleic Acids Research, 48(16), 8848–8869. https://doi.org/10.1093/nar/gkaa666
Shen, J., Wang, Q., Mao, Y., Gao, W., & Duan, S. (2023). Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies. MedComm, 4(3), e288. https://doi.org/10.1002/mco2.288
Wang, X., Duong, L., Qin, Y., Parrotta, R., Purohit, P. K., Fang, Y., Liu, G., He, J., Wen, J., Liu, Y., Zhang, Y., Zhao, J., Schafer, Z. T., Xuemin Lu, Szegezdi, E., & Lu, X. (2025). Synthetic essentiality of TRAIL/TNFSF10 in VHL-deficient renal cell carcinoma. bioRxiv, 2025.05.29.621197. https://doi.org/10.1101/2025.05.29.621197
Yuan, X., Gajan, A., Chu, Q., Xiong, H., Wu, K., & Wu, G. S. (2018). Developing TRAIL/TRAIL-death receptor-based cancer therapies. Cancer Metastasis Reviews, 37(4), 733–748. https://doi.org/10.1007/s10555-018-9728-y
Zhang, H., Xu, J., Long, Y., Maimaitijiang, A., Su, Z., Li, W., & Li, J. (2024). Unraveling the Guardian: P53’s Multifaceted Role in the DNA Damage Response and Tumor Treatment Strategies. International Journal of Molecular Sciences, 25(23), 12928. https://doi.org/10.3390/ijms252312928
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