Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

Wang, Li; Ni, Zhaofei; Liu, Yujie; Ji, Shuang; Jin, Fuquan; Jiang, Keguo; Ma, Jingdong; Ren, Chao; Zhang, Hongbing; Hu, Zhongdong; Zha, Xiaojun

doi:10.18632/oncotarget.18963

Cited by 6 publications

(13 citation statements)

References 59 publications

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“…Subcutaneous tumors were established in nude mice as described previously 23 . Immunodeficient BALB/c nude male mice (16-18 g, 5 weeks) were purchased from Vital River Laboratories Animal Technology (Beijing, China).…”

Section: Induction Of Subcutaneous Tumors and Combination Treatment Wmentioning

confidence: 99%

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AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development

et al. 2021

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As evidenced by the behavior of loss-of-function mutants of PTEN in the context of a gain-of-function mutation of AKT1, the PTEN-AKT1 signaling pathway plays a critical role in human cancers. In this study, we demonstrated that a deficiency in PTEN or activation of AKT1 potentiated the expression of platelet-derived growth factor receptor α (PDGFRα) based on studies on Pten−/− mouse embryonic fibroblasts, human cancer cell lines, the hepatic tissues of Pten conditional knockout mice, and human cancer tissues. Loss of PTEN enhanced PDGFRα expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFRα expression by direct binding of the promoter of the PDGFRα gene. Depletion of PDGFRα attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFRα expression in multiple cancers. Augmented PDGFRα was associated with poor survival of cancer patients. Lastly, combination treatment with the AKT inhibitor MK-2206 and the PDGFR inhibitor CP-673451 displayed synergistic anti-tumor effects. Therefore, activation of the AKT1-CREB-PDGFRα signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.

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Section: Induction Of Subcutaneous Tumors and Combination Treatment Wmentioning

confidence: 99%

“…Immunohistochemical analysis was performed as described previously 23 . In brief, tumor tissues were fixed in 4% paraformaldehyde and embedded in paraffin.…”

Section: Immunohistochemistry (Ihc) Analysismentioning

confidence: 99%

AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development

et al. 2021

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“…The benign feature of TSC-associated tumors has been, at least in part, attributed to the loss of Akt signaling due to either a mTORC1-dependent negative feedback regulation of Akt and the attenuation of mTORC2 signaling derived from the loss of TSC1/2 complex function [ 82 , 83 ]. More recently, other studies demonstrating that hyperactivated mTORC1-dependent Akt inhibition constrains tumor growth in TSC patients by downregulation of different signaling cascades, have been reported [ 84 , 85 ]. Jin et al also reported a hyperactivated mTORC1-independent protective effect against malignant tumor development in TSC induced by downregulation of the SOX9-OPN signaling cascade through the inhibition of Akt [ 86 ].…”

Section: Mtorc1 Signaling Pathway and Disease: The Tuberous Scleromentioning

confidence: 99%

“…The benefit of the combined treatment was also demonstrated in a TSC xenograft mouse model [ 153 ]. Wang et al showed that in both Tsc1 - and Tsc2 -null MEFs the hyperactivation of mTORC1 drives Akt inhibition through the downregulation of FOXO3a/PDGFRα pathway [ 84 ]. Rapamycin treatment led to the upregulation of PDGFRα that has been associated with the increase in tumorigenesis in Tsc1 - or Tsc2 -knockout MEFs.…”

Section: Therapeutic Strategies For Tuberous Sclerosis Complexmentioning

confidence: 99%

mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model

Polchi

Magini

Meo

et al. 2018

IJMS

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The mechanistic target of rapamycin (mTOR), a serine-threonine kinase, plays a pivotal role in regulating cell growth and proliferation. Notably, a great deal of evidence indicates that mTOR signaling is also crucial in controlling proliferation and differentiation of several stem cell compartments. Consequently, dysregulation of the mTOR pathway is often associated with a variety of disease, such as cancer and metabolic and genetic disorders. For instance, hyperactivation of mTORC1 in neural stem cells (NSCs) is associated with the insurgence of neurological manifestation characterizing tuberous sclerosis complex (TSC). In this review, we survey the recent contributions of TSC physiopathology studies to understand the role of mTOR signaling in both neurogenesis and tumorigenesis and discuss how these new insights can contribute to developing new therapeutic strategies for neurological diseases and cancer.

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“…The balance of the PI3K signaling pathway is pivotal to maintain the growth and survival of the primordial follicle pool [32]; a rodent model revealed that the PI3K/AKT pathway mediated oocyte apoptosis and FoxO3a plays an important role in early follicular development [29]. Furthermore, FoxO3a was found to maintain the PTEN-PI3K-AKT-FoxO3a pathway, enabling faster follicle growth [33]. Previous researchers have found that locally produced NO and the NOS/sGC pathway might be involved in the maturation of the follicles [34,35].…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Synthase Is Involved in Follicular Development via the PI3K/AKT/FoxO3a Pathway in Neonatal and Immature Rats

Zhang

Zhu

et al. 2020

Animals

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It is assumed that nitric oxide synthase and nitric oxide are involved in the regulation of female reproduction. This study aimed to assess the roles of nitric oxide synthase (NOS) in follicular development. The endothelial NOS (eNOS) inhibitor L-NAME, inducible NOS (iNOS) inhibitor S-Methylisothiourea (SMT) and NOS substrate L-arginine (L-Arg) were used in the NOS inhibition models in vivo. Neonatal female rats were treated with phosphate buffer saline (PBS, control), L-NAME (L-NG-Nitroarginine Methyl Ester, 40 mg/kg), SMT (S-Methylisothiourea, 10 mg/kg), L-NAME + SMT, or L-Arg (L-arginine, 50 mg/kg) via subcutaneous (SC) injection on a daily basis for 19 consecutive days, with the samples being collected on specific postnatal days (PD5, PD10, and PD19). The results indicated that the number of antral follicles, the activity of total-NOS, iNOS, neuronal NOS (nNOS), and eNOS, and the content of NO in the ovary were significantly (p < 0.05) increased in the L-Arg group at PD19, while those in L + S group were significantly (p < 0.05) decreased. Meanwhile, the ovarian expression in the L-Arg group in terms of p-AKT, p-FoxO3a, and LC3-II on PD19 were significantly (p < 0.05) upregulated, while the expressions of PTEN and cleaved Caspase-3 were (p < 0.05) downregulated as a result of NOS/NO generation, respectively. Therefore, the results suggest that NOS is possibly involved in the maturation of follicular development to puberty via the PI3K/AKT/FoxO3a pathway, through follicular autophagia and apoptosis mechanisms.

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Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

Cited by 6 publications

References 59 publications

AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development

AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development

mTOR Signaling and Neural Stem Cells: The Tuberous Sclerosis Complex Model

Nitric Oxide Synthase Is Involved in Follicular Development via the PI3K/AKT/FoxO3a Pathway in Neonatal and Immature Rats

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