Abstract
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.
Highlights
Leukemia is characterized by the uncontrolled proliferation of abnormal white blood cells and is divided into four main subtypes: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL) [1]
We revealed that GBP1 and GBP2 are apoptosis-inducing molecules that activate caspases 3, 8, and 9, and further delineated their underlying mechanism for the first time
In the case of T-cell acute lymphoblastic leukemia (T-ALL), one study showed that ZSTK-474, a pan PI3K p110 inhibitor, decreased BAK
Summary
Leukemia is characterized by the uncontrolled proliferation of abnormal white blood cells and is divided into four main subtypes: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphocytic leukemia (CLL) [1]. The GBP2-induced regulation of BAK expression was confirmed at BAK protein level in HL-60 cells, while the levels of BAX and MCL-1 were not altered by GBP2 (Fig. 3h) These observations prompted us to determine the expression change of the BAK mRNA transcript following the modulation of GBP2 levels. The cell cycle arrest-promoting activity of paclitaxel was not affected by GBP2 silencing (Fig. 5h) These data indicate that GBP2 is a key mediator of the apoptotic function of paclitaxel in K562 cells. LY294002-mediated inhibition of AKT phosphorylation increased GBP2 levels to some degree, paclitaxel was still able to dramatically increase GBP2 expression in AKT-inactivated cells (Supplementary Fig. 10a) These results suggest that paclitaxelinduced GBP2 upregulation is not dependent on its AKT inactivation activity. GBP2 and GBP5 expression levels did not show significant benefit to leukemia and lymphoma patients, high expression of GBP2 and GBP5 showed trends of better prognosis in the long term (Fig. 6c)
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