Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway

Burris, Howard A.

doi:10.1007/s00280-012-2043-3

Cited by 379 publications

(289 citation statements)

References 101 publications

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“…23 Given the capacity of IKK-related kinases TBK1 and IKKe to directly phosphorylate AKT, [24][25][26] we aimed to identify new TBK1 substrates through interactomic studies to better understand the molecular link between TBK1 and AKT. We conducted a yeast two-hybrid screen using the C-terminal domain of TBK1 (amino acids 529-729) fused to the DNA-binding domain of the GAL4 transcription factor as bait ( Figure 1a).…”

Section: Hpip Is a Tbk1-interacting Proteinmentioning

confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubuleassociated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53-dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels. Cell Death and Differentiation (2014) 21, 811-824; doi:10.1038/cdd.2014.2; published online 31 January 2014Restoration of p53 tumor suppressor function in cancer cells expressing wild-type (WT) p53 is a promising therapeutic approach. 1 Reactivation of p53 activity can be achieved by small molecular inhibitors that disrupt the interaction between p53 and its main E3 ligase MDM2. As a result, targeted cells undergo cell cycle arrest and apoptosis through p53 stabilization. 2 A potential drawback associated with this approach is that, besides p53, MDM2 targets other substrates for degradation. 3 In this context, accumulative evidence show that MDM2 promotes the degradation of FOXO3a, a tumor-suppressing transcription factor as well as the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. 4,5 Although it is currently unclear whether MDM2 targets positive regulators of oncogenic pathways, an exhaustive characterization of MDM2 substrates will help to anticipate undesired side effects of MDM2 inhibitors used in cancer therapy.Oncogenic pathways include AKT-dependent signaling cascades. Indeed, AKT promotes cell proliferation, survival, migration and angiogenesis by targeting numerous substrates ranging from anti-apoptotic transcription factors to regulators of protein synthesis. 6,7 Mutations or altered expressions of various AKT-activating signaling molecules have been described in human malignancies, thereby defining AKT as a hallmark of tumor development and progression. 8,9 AKT activation by estrogens requires the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). 10 Initially identified as a corepressor of pre-B-cell leukemia homeobox protein 1 (PBX1), 11 HPIP assembles a signaling complex that connects the p85 subunit of PI3K and ERa to microtubules in order to properly activate AKT. 10 Likewise, HPIP also promotes the growth and differentiation of hematopoietic cells through AKT. 12 Because correct reg...

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Section: Hpip Is a Tbk1-interacting Proteinmentioning

confidence: 99%

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

et al. 2014

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“…This signaling pathway contributes to cell proliferation, differentiation, metabolism, cytoskeletal reorganization and apoptosis (28). Activation of the PI3K/AKT/mTOR signaling pathway promotes cancer cell survival and therapy resistance (29)(30)(31). Following activation of the PI3K/AKT/mTOR signaling pathway by membrane tyrosine kinase growth factor receptors or G protein-coupled receptors (32,33), functional PI3K is translocated to the plasma membrane where it causes the phosphorylation of phosphatidylinositol 3,4,5-triphosphate (PIP3) (33).…”

Section: Discussionmentioning

confidence: 99%

AXIN1 protects against testicular germ cell tumors via the PI3K/AKT/mTOR signaling pathway

Yan

Jia

et al. 2017

Oncology Letters

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Abstract. Axis inhibition protein 1 (AXIN1) is characterized as a tumor suppressor in numerous types of cancer. However, the functional role of AXIN1 in the testicular germ cell tumors (TGCTs) remains unclear. The human embryonal carcinoma-derived cell line NTera2 was transfected with a recombinant AXIN1 expression vector (pcDNA3.1-AXIN1) and/or a small interfering RNA (siRNA) directed against AXIN1 (siAXIN). Following transfection, the mRNA and protein levels of AXIN1 were determined via reverse transcription-quantitative polymerase chain reaction analysis and western blotting, respectively. In addition, cell viability, apoptosis and the expression of apoptosis-associated proteins [apoptosis regulator Bax (Bax) and B-cell lymphoma (Bcl)-2] and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway proteins [phosphorylated (p)-mTOR, mTOR, p-AKT, AKT, P-70S ribosomal protein S6 (S6) and S6] were assessed. AXIN1 mRNA and protein levels were increased following transfection with pcDNA3.1-AXIN1 and decreased following transfection with siAXIN1 compared with their respective control groups. After overexpression of AXIN1, NTera2 cell viability and expression of Bcl-2, p-mTOR p-AKT and p-S6 protein was decreased, while apoptosis and Bax protein levels were increased, compared with the control group. However, there was no significant difference in AXIN1 mRNA expression, apoptosis or Bax/Bcl-2 protein expression when NTera2 cells were simultaneously transfected with pcDNA3.1-AXIN1+siAXIN1. In conclusion, the results of the present study indicate that overexpression of AXIN1 protects against TGCTs via inhibiting the PI3K/AKT/mTOR signaling pathway, suggesting that AXIN1 may be a potential target for gene therapy in TGCTs.

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“…The development of targeted therapies against PI3K/AKT/mTOR pathway at multiple levels could be helpful for the treatment of many cancer types. The inhibition of this pathway potentially has suppressed tumor survival and in combination with other anticancer therapies circumvents resistance in cancer cells (10).…”

Section: Introductionmentioning

confidence: 99%

Combined Application of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Inhibitors Suppresses Cell Growth and Promotes Apoptosis in Human Lung Cancer Cell Lines

Badinloo

Esmaeili‐Mahani

2016

Iran J Cancer Prev

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PI3K/Akt/mTOR would be an important intracellular signal pathway which has found to be over-activated in neoplasia. Here, the combination effect of LY294002 (PI3K inhibitor) and rapamycine (mTOR inhibitor) has evaluated in different human lung cancer cell lines. MTT assay has used to assess the viability of Calu-6, SK-MES-1 and A549 cancer cells. The levels of biochemical markers of apoptosis (activated caspase-3) and cell proliferation (c-Myc and cyclin D1) have evaluated by immunoblotting. The data has shown that blockade of PI3K/Akt cascade with LY294002 (0.1-100 µM) resulted in growth inhibition with IC50 ranging from 7 to 35 µM.LY294002 plus rapamycin (10 nM) significantly enhanced the growth inhibition rate and elevated cleaved caspase-3 in A549 and SK-MES-1 cells. Moreover, such combination therapy had a potent decreasing effect on c-Myc and cyclin D1 protein levels. Taken together, combined inhibition of PI3K/Akt/mTOR signaling has represented a promising treatment strategy for lung cancer but the effectiveness of such combination therapy has been depending on the cancer cell types.

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Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway

Abstract: Current preclinical and clinical evidence suggest that inhibitors of the PI3K/AKT/mTOR pathway could have utility in combination with other anticancer therapies to circumvent resistance by cancer cells. Multiple clinical studies are ongoing.

Cited by 379 publications

References 101 publications

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation

AXIN1 protects against testicular germ cell tumors via the PI3K/AKT/mTOR signaling pathway

Combined Application of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Inhibitors Suppresses Cell Growth and Promotes Apoptosis in Human Lung Cancer Cell Lines

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