Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression

Abstract

Background: Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL). Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models. Methods: The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined. Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated in vitro. The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells. The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients. Results: AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax. Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax. Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation. Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth in vivo, which was dependent on FOXO1. In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1. Conclusions: Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis. Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.

LINC00493‐encoded microprotein SMIM26 exerts anti‐metastatic activity in renal cell carcinoma

“…In contrast, the silence of SMIM26 decreased the level of mitochondrial AGK (Fig EV5A). Literature reported that AGK phosphorylated PTEN to restrict its function of activating AKT (Hu et al , 2019; Ning et al , 2022). Overexpression of AGK increased the mitochondrial and non‐mitochondrial AGK levels (Fig EV5B).…”

Tumor cell metabolic reprogramming and hypoxic immunosuppression: driving carcinogenesis to metastatic colonization

“…As a result, immune cells like CD8+ T cells must develop and maintain metabolic fitness in order to respond to unfavorable metabolic circumstances ( Figure 5 ). Acylglycerol kinase (AGK) positively regulates PTEN (phosphatase and tensin homolog) phosphorylation and inhibits PTEN’s phosphatase activity in CD8+ T cells when PTEN accumulates on the plasma membrane through the mediation of TCR and CD28, promoting activation of PI3K-mTOR modulating glycolysis, and controlling anti-tumor activity ( 82 ). In terms of functionality, AGK is essential for preserving CD8+ T cells’ metabolic fitness in the TME ( 83 ).…”

FoxO1 promotes ovarian cancer by increasing transcription and METTL14‐mediated m6A modification of SMC4

“…Forkhead box protein O1 (FoxO1), which is also known as forkhead rhabdomyosarcoma transcription factor, belongs to the forkhead box O (FoxO) transcription factor family and is in the center of the tumor molecular regulatory network 6,7 . Numerous studies have shown that the imbalance of FoxO1 is closely related to the pathological process of tumor development, invasion, and metastasis 7–11 . However, there is no unified conclusion about the effect of FoxO1 in OC.…”

“… 6 , 7 Numerous studies have shown that the imbalance of FoxO1 is closely related to the pathological process of tumor development, invasion, and metastasis. 7 , 8 , 9 , 10 , 11 However, there is no unified conclusion about the effect of FoxO1 in OC. Some studies have shown that FoxO1 has a tumor suppressor role in OC.…”