MLLT11-TRIL complex promotes the progression of endometrial cancer through PI3K/AKT/mTOR signaling pathway

Abstract

Endometrial cancer (EC) is a gynecological malignant tumor characterized by high incidence. EC occurrence and development are regulated by numerous molecules and signal pathways. There is a need to explore key regulatory molecules to identify potential therapeutic targets to reduce the incidence of EC. Treatment by targeting a single molecule is characterized by poor efficacy owing to the development of resistance and significant side effects. The current study explored potential candidates in EC by integrating bioinformatics analysis and in vivo and in vitro experimental validation to circumvent the limitation of low efficacy of currently used molecules. Molecular dynamics simulations provide details at the molecular level of intermolecular regulation. In the current study, MLLT11 and TRIL were identified as important regulatory molecules in EC. The two molecules formed a heteromultimer by binding to AKT protein, which induced its phosphorylation of threonine at position 308. Ultimately, the complex stimulates PI3K/AKT/mTOR signaling pathway, a pivotal pathway in tumors. The findings of the current study show a novel complex, MLLT11-TRIL, which can act as AKT protein agonist, thus inducing activity of PI3K/AKT/mTOR signaling pathway. Targeting MLLT11 and TRIL simultaneously, or blocking the formation of the MLLT11-TRIL complex, can abrogate progression of EC.

Novel biomarkers predict prognosis and drug-induced neuroendocrine differentiation in patients with prostate cancer

“…Consequently, it is worth exploring the relationship between HMGN2 and JAK2-STAT5A/B pathway. Involvement of MLLT11 promoted the progression of ovarian cancer, bladder cancer and endometrial cancer in previous study (77,78). Moreover, the granule protein family member PCSK1N, also known as ProSAAS, is a protein produced almost entirely by a wide variety of endocrine, neuronal and neuroendocrine cells (79,80).…”

MLLT11 Regulates Endometrial Stroma Cell Adhesion, Proliferation and Survival in Ectopic Lesions of Women with Advanced Endometriosis

“…MLLT11 is a gene implicated in hematopoietic progenitor cell differentiation [ 31 ] and neuronal cell differentiation [ 32 ]. In a pathogenic context, MLLT11 has been reported to play an oncogenic role in the development and progression of a variety of human cancers [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ] and to act as a tumor suppressor in glioma neural carcinomas [ 21 ]. However, the role for MLLT11 in the pathogenesis of endometriosis has not been previously reported.…”

“…On the other hand, MLLT11 has also been identified as mediator of basal and 4-HPR-induced apoptosis in ovarian cancer cells, illustrating the somewhat contradictory dual proapoptotic and protumorigenic behavior of the gene in ovarian cancer cells [16]. A functional role of MLLT11 in tumor progression was also reported in human breast [17] and endometrial carcinomas [18], as well as in a number of other human solid tumors [19,20]. In contrast to this oncogenic role, in the nervous system, MLLT11 functions as a tumor suppressor, with a high level of expression in normal brain tissues compared with decreased expression correlating with the malignant tumor grade [21].…”

New insights for gynecological cancer therapies: from molecular mechanisms and clinical evidence to future directions

“…Mechanisms underlying abnormal PI3K/AKT/mTOR pathway activation include amplification or mutation of PI3K/AKT, activation of growth factor receptors, loss function of tumor suppressor PTEN, and exposure to carcinogens [ 186 ]. Through a diverse set of downstream targets, the PI3K/AKT/mTOR pathway responds to several endogenous or exogenous stimuli to determine EC cell fate and AKT can be catalytically activated by the MLLT11-TRIL complex, which promotes cancer progression [ 187 ]. In EC, PI3K/AKT/mTOR inhibition is responsible for metformin-induced cell proliferation, while its activation promotes progestin resistance [ 188 , 189 ].…”