Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy

Xu, Zhenru; Han, Xu; Ou, Daming; Liu, Ting; Li, Zunxiong; Jiang, Guanmin; Liu, Jing; Zhang, Ji

doi:10.1007/s00253-019-10257-8

Cited by 416 publications

(296 citation statements)

References 109 publications

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“…The PI3K/AKT/mTOR pathway is one of the most frequently activated signaling pathways in cancers and is responsible for tumor development, cellular metastasis, and proliferation (Polivka and Janku, 2014;Zhang et al, 2017;Chamcheu et al, 2019). In particular, the PI3K/AKT/mTOR pathway has attracted extensive attention as the modulator of autophagy (Xu et al, 2020). The central checkpoint for the negative regulation of autophagy is mTOR, and anti-tumor drugs stimulate autophagy by attenuating the PI3K/AKT/mTOR pathway (Janku et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma

Chen

Wang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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Radiotherapy is a conventional and effective treatment method for nasopharyngeal carcinoma (NPC), although it can fail, mainly because radioresistance results in residual or recurrent tumors. However, the mechanisms and predictive markers of NPC radioresistance are still obscure. In this study, we identified Annexin A6 (ANXA6) as a candidate radioresistance marker by using Tandem Mass Tag quantitative proteomic analysis of NPC cells and gene chip analysis of NPC clinical samples with different radiosensitivities. It was observed that a high expression level of ANXA6 was positively correlated with radioresistance of NPC and that inhibition of ANXA6 by siRNA increased the radiosensitivity. The incidence of autophagy was enhanced in the established radioresistant NPC cells in comparison with their parent cells, and silencing autophagy with LC3 siRNA (siLC3) sensitized NPC cells to irradiation. Furthermore, ANXA6 siRNA (siANXA6) suppressed cellular autophagy by activating the PI3K/AKT/mTOR pathway, ultimately leading to radiosensitization. The combination of siANXA6 and CAL101 (an inhibitor of PI3K, p-AKT, and mTOR, concurrently) significantly reversed the above siANAX6-reduced autophagy. Suppression of PI3K/AKT/mTOR by CAL101 also increased the expression of ANXA6 in a negative feedback process. In conclusion, this study revealed for the first time that ANXA6 could promote autophagy by inhibiting the PI3K/AKT/mTOR pathway and that it thus contributes to radioresistance of NPC. The significance of this is that ANXA6 could be applied as a new predictive biomarker of NPC prognosis after radiotherapy.

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Section: Discussionmentioning

confidence: 99%

ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma

Chen

Wang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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“…Autophagy can promote cell adaption and survival, but it also leads to cell death under particular conditions. Autophagy is a double-edged sword for drug resistance, as growing evidence indicates that autophagy can contribute to resistance against chemotherapeutics [ 88 ]. In recent years, it has become evident that autophagy might be critical in GIST progression.…”

Section: Influence Of the Pi3k/akt/mtor Pathway On Proliferation mentioning

confidence: 99%

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

Duan

Haybaeck

Yang

2020

Cancers

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Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.

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“…Since E2F2 can regulate the PI3K/Akt/mTOR pathway, which play an important role in affecting autophagy (28,29), we further examined the relationship between E2F2 and autophagy-related protein expression in GC cells that were transfected with GV141-EE2F2 or siE2F2. We found that the expression levels of LC3II decreased most markedly after E2F2 was overexpressed, while P62 protein expression was signi cantly increased ( Figure 7A).…”

Section: Effects Of E2f2 Expression Levels On Gc Cell Migration and Imentioning

confidence: 99%

E2F2 inhibition induces autophagy to impair metastasis via the PI3K/Akt/mTOR pathway in gastric cancer

Zhao

Shen

et al. 2020

Preprint

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Background: E2F2 is a member of the E2F family of transcription factors with important yet incompletely understood biological functions in cancer. In some cancer types, controversial tumor-promoting and tumor-suppressive roles of E2F2 have been reported. However, the biological role of E2F2 in gastric cancer (GC) remains to be determined. Methods: We analyzed E2F2 expression via multiple gene expression databases. The prognostic value of the E2F2 was determined by Kaplan-Meier Plotter and Cox regression. The correlations between E2F2 and cancer immune infiltrates were investigated via Tumor Immune Estimation Resource (TIMER). The functions and pathways of E2F2 and its 50 frequently changed genes closely associated with the family members were analyzed using Database for Annotation, Visualization, and Integrated Discovery (DAVID) software. We used immunohistochemistry (IHC), quantitative real-time PCR (qPCR) and western blot to verify the expression level of E2F2 in GC and further studied the effects of E2F2 on PI3K/Akt/mTOR activity; GC cell autophagy, migration, and invasion through wound healing assays, transwell assays, Western blotting, and transmission electron microscopy.Results: We observed that compared with normal gastric tissues/cells, E2F2 is highly expressed in gastric cancer tissues and cells in both the public datasets and in our experimental verification. High E2F2 expression was associated with poorer overall survival (OS). Moreover, E2F2 expression showed strong correlations with diverse immune marker sets in GC. Moreover, E2F2 overexpression promoted GC cell migration and invasion in vitro by inactivating PI3K/Akt/mTOR-mediated autophagy. Conversely, E2F2 inhibition suppressed GC cell migration and invasion in vitro by activating PI3K/Akt/mTOR-mediated autophagy.Conclusions: In conclusion, this study provides multi-level evidence for the importance of E2F2 in gastric carcinogenesis and its potential as a biomarker in GC. We demonstrated that E2F2 is overexpressed in GC and that high E2F2 expression is associated with aggressive tumor features and poorer patient prognosis. Further, our results suggest a potential novel immune regulatory role of E2F2 in tumor immunity. Functionally, we discovered a new role of E2F2 in regulating PI3K/Akt/mTOR-mediated autophagy and the downstream processes of cell migration and invasion. Our results could potentially reveal new targets and strategies for GC diagnosis and treatment.

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Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy

Cited by 416 publications

References 109 publications

ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma

ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

E2F2 inhibition induces autophagy to impair metastasis via the PI3K/Akt/mTOR pathway in gastric cancer

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