ISSN: 1449-1907International Journal of Medical Sciences
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Int J Med Sci 2024; 21(1):70-79. doi:10.7150/ijms.84952 This issue Cite
Research Paper
Anlotinib suppresses the DNA damage response by disrupting SETD1A and inducing p53-dependent apoptosis in Transformed Follicular Lymphoma
1. Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China.
2. Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361102, China.
3. Department of Clinical Laboratory, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
†These authors contributed equally to this work.
Abstract
Purpose: The high tumor mutational burden (TMB) of transformed follicular lymphoma (tFL) leads to tumor heterogeneity and poor prognosis in follicular lymphoma, in which endogenous DNA damage and epigenetic modification are the key factors. This study aims to evaluate the efficacy of anlotinib in tFL and to investigate its potential therapeutic mechanism.
Methods: Cell viability and apoptosis were tested with CCK-8 and annexin V/PI staining kits, respectively. The tumorigenicity test in mice was utilized to further confirm the efficacy of anlotinib in vivo. Western blotting was utilized to explore the molecular mechanisms.
Results: Anlotinib induced G2/M phase arrest in tFL cells, inhibited the proliferation of tFL cells and promoted the apoptosis of tFL cells in a dose-dependent manner. Administration of anlotinib markedly reduced tumor mass and weight in an FL xenograft mouse model. The western blot and immunohistochemistry staining results confirmed that the mechanism by which anlotinib promoted tumor cell apoptosis was DNA damage. Further results showed that anlotinib significantly downregulated the expression of SETD1A, leading to its destruction. Anlotinib administration resulted in a significant dose-dependent increase in the level of p-p53. Furthermore, anlotinib greatly downregulated the antiapoptotic proteins Mcl-1 and in parallel upregulated the proapoptotic element BAX and Bak, accompanied by caspase-3 activation and PARP degradation.
Conclusion: Anlotinib has a good proapoptotic effect on tumor cells in vitro and in vivo, and its possible mechanism is related to the inhibition of the DNA damage response by disrupting SETD1A.
Keywords: Transformed follicular lymphoma (tFL), Anlotinib, SETD1A, DNA damage response, p53
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