TCP1 increases drug resistance in acute myeloid leukemia by suppressing autophagy via activating AKT/mTOR signaling.

T-complex protein 1 (TCP1) is one of the subunits of chaperonin-containing T complex (CCT), which is involved in protein folding, cell proliferation, apoptosis, cell cycle regulation, and drug resistance. Investigations have demonstrated that TCP1 is a factor being responsible for drug resistance in breast and ovarian cancer. However, the TCP1 role in acute myeloid leukemia (AML) remains elusive. In the present study, we discovered that the TCP1 expression was elevated in AML patients and high TCP1 expression was associated with low complete response rate along with poor overall survival. TCP1 showed higher expression in the adriamycin-resistant leukemia cell line HL60/A and K562/A, comparing to their respective parent cells HL60 and K562 cells. TCP1 inhibition suppressed drug resistance in HL60/A and K562/A cells, whereas TCP1 overexpression in HL60 cells incremented drug resistance, both in vitro and in vivo. Mechanistic investigations revealed that TCP1 inhibited autophagy and adriamycin-induced cell apoptosis, and TCP1-mediated autophagy inhibition conferred resistance to adriamycin-induced cell apoptosis. Furthermore, TCP1 interacted with AKT and mTOR to activate AKT/mTOR signaling, which negatively regulates apoptosis and autophagy. Pharmacological inhibition of AKT/mTOR signal particularly activated autophagy and resensitized TCP1-overexpressing HL60 cells to adriamycin. These findings identify a novel role of TCP1 regarding drug resistance in AML, which advise a new strategy for overcoming drug resistance in AML through targeting TCP1/AKT/mTOR signaling pathway.

Chen X ，Chen X ，Huang Y ，Lin J ，Wu Y ，Chen Y ... -  《Cell Death & Disease》

TCP1 regulates PI3K/AKT/mTOR signaling pathway to promote proliferation of ovarian cancer cells.

Weng H ，Feng X ，Lan Y ，Zheng Z ... -  《Journal of Ovarian Research》

[The Effect of TCP1 Expression on the Proliferation and the Accumulation of Intracellular Drug of HL60/A and HL60 Cell and Its Mechanism].

Chen XF ，Chen XL ，Chen YZ 《-》

METTL14-mediated N6-methyladenosine modification of TCP1 mRNA promotes acute myeloid leukemia progression.

Acute myeloid leukemia (AML) is a prevalent hematologic malignancy characterized by a steady rise in morbidity and mortality rates over time. The upregulation of methyltransferase-like 14 (METTL14) expression in AML has been identified; however, its specific contributions to AML progression and underlying molecular mechanisms have yet to be elucidated. METTL14-bound mRNAs were predicted using bioinformatics methods, analyzed, and screened to identify T-complex protein 1 (TCP1). The regulatory impact of METTL14 on TCP1 was observed. TCP1 expression in AML clinical samples was assessed using quantitative real-time PCR and western blot analysis. The involvement of TCP1 in AML malignant progression was assessed through in vitro and in vivo functional assays. The String database was utilized for predicting proteins that interact with TCP1, while western blot assays and immunoprecipitation were employed to validate the associated signaling pathways. METTL14 overexpression upregulates TCP1 expression in AML cells. AML patients exhibit high levels of TCP1 expression. Elevated TCP1 levels in HL60 and U937 cells in vitro lead to increased proliferation, migration, invasion, and inhibition of apoptosis, while in vivo, it accelerates AML proliferation and tumorigenesis. Mechanistically, METTL14 modulates AML progression by influencing TCP1 transcript stability via m6A methylation, thereby regulating TCP1 expression. Additionally, PPP2R2C potentially serves as a crucial functional target of TCP1 implicated in the malignant progression of AML. Upregulation of TCP1 expression in AML through METTL14-mediated m6A modification accelerates the malignant progression of the disease. Therefore, targeting the m6A modification of TCP1 could be a potential therapeutic strategy to enhance the treatment of AML.

Zhang M ，Xie Z ，Tan Y ，Wu Y ，Wang M ，Zhang P ，Yuan Y ，Li J ... -  《-》

A combination of temsirolimus, an allosteric mTOR inhibitor, with clofarabine as a new therapeutic option for patients with acute myeloid leukemia.

Chiarini F ，Lonetti A ，Teti G ，Orsini E ，Bressanin D ，Cappellini A ，Ricci F ，Tazzari PL ，Ognibene A ，Falconi M ，Pagliaro P ，Iacobucci I ，Martinelli G ，Amadori S ，McCubrey JA ，Martelli AM ... -  《Oncotarget》