Guanylate-binding proteins induce apoptosis of leukemia cells by regulating MCL-1 and BAK
Autor: | Yongyang Luo, Hanyong Jin, Je Hyeong Kim, Jeehyeon Bae |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cell death Cancer Research GBP2 Biology medicine.disease_cause DNA-binding protein Article 03 medical and health sciences 0302 clinical medicine Mediator hemic and lymphatic diseases medicine Molecular Biology PI3K/AKT/mTOR pathway RC254-282 Haematological cancer Myeloid leukemia Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Leukemia 030104 developmental biology Apoptosis 030220 oncology & carcinogenesis Cancer research Carcinogenesis |
Zdroj: | Oncogenesis, Vol 10, Iss 7, Pp 1-12 (2021) Oncogenesis |
ISSN: | 2157-9024 |
Popis: | Interferon-inducible guanylate-binding proteins (GBPs) are well-known for mediating host-defense mechanisms against cellular pathogens. Emerging evidence suggests that GBPs are also implicated in tumorigenesis; however, their underlying molecular mechanism is still unknown. In this study, we identified that GBP1 and GBP2 interact with MCL-1, the key prosurvival member of the BCL-2 family, via its BH3 domain. GBPs induce caspase-dependent apoptosis in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cells, where the proapoptotic BCL-2 member, BAK, is an indispensable mediator. In particular, GBP2 completely inhibited the MCL-1-mediated promotion of the survival of CML cells through competitive inhibition, resulting in BAK liberation from MCL-1. Concurrently, GBP2 dramatically upregulates BAK expression via its inhibition of the PI3K/AKT pathway. Moreover, paclitaxel upregulates GBP2 expression, and paclitaxel-induced apoptotic activity was distinctively compromised by knockout of GBP2 in CML cells. Bioinformatics analyses of leukemia databases revealed that transcripts of GBPs were generally downregulated in leukemia patients and that GBPs were favorable prognosis markers. Thus, these findings provide molecular evidence of GBPs as apoptosis-inducing proteins of leukemia cells and suggest that GBPs are attractive targets for the development of chemotherapeutics. |
Databáze: | OpenAIRE |
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