Targeting Akt/PKB in pediatric tumors: A review from preclinical to clinical trials

Toson, Bruno; Fortes, Isadora S.; Roesler, Rafaël; Andrade, Saulo Fernandes de

doi:10.1016/j.phrs.2022.106403

Cited by 19 publications

(19 citation statements)

References 173 publications

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“…No UHRF1-targeted inhibitor has been testing in clinic trials, while several AKT phosphorylation inhibitors have been developed, and demonstrated significant anticancer efficacy in the pre-clinical or clinical trials [ 36 , 37 ]. We proposed whether AKT phosphorylation inhibitor destroyed the protein stability of UHRF1.…”

Section: Resultsmentioning

confidence: 99%

AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer

Cao

Zou

et al. 2023

Oncogenesis

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Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations are the characters of castration-resistant prostate cancer (CRPC). UHRF1 as a key epigenetic regulator, plays a critical role in prostate cancer (PCa) development, and its expression is positively correlated with the degree of malignancy. In this present study we investigated the potential regulatory mechanism of AKT1 on UHRF1, and further validated the in vitro and in vivo anticancer efficacy of AKT phosphorylation inhibitor MK2206 in combination with abiraterone. Both UHRF1 and p-AKT aberrantly overexpressed in the abiraterone-resistant PCa cells. Further studies revealed that AKT1 protein interacts with UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr-210. MK2206 induced UHRF1 protein degradation by inhibiting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinase USP7, while promoted the interaction between UHRF1 and E3 ubiquitin protein ligase BTRC. MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by decreasing UHRF1 protein level, and reversed the phenotype of NEPC, evently induced cellular senescence and cell apoptosis. Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3K/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3K/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.

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Section: Resultsmentioning

confidence: 99%

AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer

Cao

Zou

et al. 2023

Oncogenesis

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“…Moreover, the activation of AKT and its downstream GSK3β and BAD was inhibited in MST4 knockdown BT474 cells ( Figure 5 b), suggesting MST4 is required for AKT and its downstream signaling pathway activation in breast cancer cells and is crucial for cancer cell survival and EMT via the MST4-AKT-BAD or MST-AKT- GSK3β signaling cascade. To further confirm this, we treated the control and MST4 high-expressing MDA-MB-231 cells with an Akt inhibitor perifosine (KRX-0401) [ 35 ]. The results indicate that perifosine effectively inhibited Akt activation, and blocked the MST4 overexpression mediated anti-apoptosis effect ( Figure 5 c), confirming that MST4 activated Akt is essential for cell survival.…”

Section: Resultsmentioning

confidence: 99%

MST4: A Potential Oncogene and Therapeutic Target in Breast Cancer

Arora

Kim

Getu

et al. 2022

Cells

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The mammalian STE 20-like protein kinase 4 (MST4) gene is highly expressed in several cancer types, but little is known about the role of MST4 in breast cancer, and the function of MST4 during epithelial-mesenchymal transition (EMT) has not been fully elucidated. Here we report that overexpression of MST4 in breast cancer results in enhanced cell growth, migration, and invasion, whereas inhibition of MST4 expression significantly attenuates these properties. Further study shows that MST4 promotes EMT by activating Akt and its downstream signaling molecules such as E-cadherin/N-cadherin, Snail, and Slug. MST4 also activates AKT and its downstream pro-survival pathway. Furthermore, by analyzing breast cancer patient tissue microarray and silicon datasets, we found that MST4 expression is much higher in breast tumor tissue compared to normal tissue, and significantly correlates with cancer stage, lymph node metastasis and a poor overall survival rate (p < 0.05). Taken together, our findings demonstrate the oncogenic potential of MST4 in breast cancer, highlighting its role in cancer cell proliferation, migration/invasion, survival, and EMT, suggesting a possibility that MST4 may serve as a novel therapeutic target for breast cancer.

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“…Surprisingly, we not only observed their enrichment in a variety of solid carcinomas, such as bladder cancer, non-small cell lung cancer, and PAAD but also revealed their enrichment in important tumour signalling axes, such as the PI3K-Akt and focal adhesion signalling pathways. The PI3K/Akt/mTOR signalling pathway affects several cellular processes, such as growth, proliferation, and survival [ 36 ]. Key factors in the pathway, particularly Akt, have emerged as potential therapeutic targets in diverse tumours.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers

Zheng

Song

2023

BMC Bioinformatics

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KCNH2 encodes the human ether-a-go-go-related gene (hERG) potassium channel and is an important repolarization reserve for regulating cardiac electrical activity. Increasing evidence suggests that it is involved in the development of various tumours, yet a thorough analysis of the underlying process has not been performed. Here, we have comprehensively examined the role of KCNH2 in multiple cancers by assessing KCNH2 gene expression, diagnostic and prognostic value, genetic alterations, immune infiltration correlations, RNA modifications, mutations, clinical correlations, interacting proteins, and associated signalling pathways. KCNH2 is differentially expressed in over 30 cancers and has a high diagnostic value for 10 tumours. Survival analysis showed that high expression of KCNH2 was associated with a poor prognosis in glioblastoma multiforme (GBM) and hepatocellular carcinoma (LIHC). Mutations and RNA methylation modifications (especially m6A) of KCNH2 are associated with its expression in multiple tumours. KCNH2 expression is correlated with tumour mutation burden, microsatellite instability, neoantigen load, and mutant-allele tumour heterogeneity. In addition, KCNH2 expression is associated with the tumour immune microenvironment and its immunosuppressive phenotype. KEGG signalling pathway enrichment analysis revealed that KCNH2 and its interacting molecules are involved in a variety of pathways related to carcinogenesis and signal regulation, such as the PI3K/Akt and focal adhesion pathways. Overall, we found that KCNH2 and its interaction molecular are expected to be immune-related biomarkers for cancer diagnosis and prognosis evaluation, and are potential regulatory targets of singalling pathways for tumour development due to their significant role in cancers.

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Targeting Akt/PKB in pediatric tumors: A review from preclinical to clinical trials

Cited by 19 publications

References 173 publications

AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer

AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer

MST4: A Potential Oncogene and Therapeutic Target in Breast Cancer

Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers

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