Combined inhibition of XIAP and autophagy induces apoptosis and differentiation in acute myeloid leukaemia

Perturbations in autophagy, apoptosis and differentiation have greatly affected the progression and therapy of acute myeloid leukaemia (AML). The role of X-linked inhibitor of apoptosis (XIAP)-related autophagy remains unclear in AML therapeutics. Here, we found that XIAP was highly expressed and associated with poor overall survival in patients with AML. Furthermore, pharmacologic inhibition of XIAP using birinapant or XIAP knockdown via siRNA impaired the proliferation and clonogenic capacity by inducing autophagy and apoptosis in AML cells. Intriguingly, birinapant-induced cell death was aggravated in combination with ATG5 siRNA or an autophagy inhibitor spautin-1, suggesting that autophagy may be a pro-survival signalling. Spautin-1 further enhanced the ROS level and myeloid differentiation in THP-1 cells treated with birinapant. The mechanism analysis showed that XIAP interacted with MDM2 and p53, and XIAP inhibition notably downregulated p53, substantially increased the AMPKα1 phosphorylation and downregulated the mTOR phosphorylation. Combined treatment using birinapant and chloroquine significantly retarded AML progression in both a subcutaneous xenograft model injected with HEL cells and an orthotopic xenograft model injected intravenously with C1498 cells. Collectively, our data suggested that XIAP inhibition can induce autophagy, apoptosis and differentiation, and combined inhibition of XIAP and autophagy may be a promising therapeutic strategy for AML.

 

Comments:

The provided information discusses the role of X-linked inhibitor of apoptosis (XIAP)-related autophagy in acute myeloid leukemia (AML) and its potential as a therapeutic target. Here's a summary of the key findings:

XIAP Expression and Prognosis: XIAP was found to be highly expressed in AML patients and correlated with poor overall survival.

XIAP Inhibition Effects: Pharmacologic inhibition of XIAP using birinapant or XIAP knockdown through siRNA reduced proliferation and clonogenic capacity of AML cells.

Autophagy and Apoptosis Induction: XIAP inhibition induced autophagy and apoptosis in AML cells, contributing to decreased cell viability.

Autophagy as a Pro-survival Signaling: The combination of birinapant with ATG5 siRNA (involved in autophagy) or the autophagy inhibitor spautin-1 increased cell death, suggesting that autophagy might have a pro-survival role in this context.

ROS Level and Differentiation: Spautin-1 enhanced reactive oxygen species (ROS) levels and myeloid differentiation in THP-1 cells treated with birinapant.

Mechanism Analysis: XIAP was found to interact with MDM2 and p53. XIAP inhibition downregulated p53, increased AMPKα1 phosphorylation, and decreased mTOR phosphorylation.

Combined Treatment: Combining birinapant with the autophagy inhibitor chloroquine significantly slowed down AML progression in both subcutaneous and orthotopic xenograft models.

Overall, the data suggests that XIAP inhibition can induce autophagy, apoptosis, and differentiation in AML cells. Additionally, combining XIAP inhibition with autophagy inhibition may be a promising therapeutic strategy for AML treatment.

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Autophagy Apoptosis related DUB