Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex

Ji, Shuang; Lin, Wei; Wang, Li; Ni, Zhaofei; Jin, Fuquan; Zha, Xiaojun; Fei, Guanghe

doi:10.7150/jca.17205

Cited by 20 publications

(23 citation statements)

References 37 publications

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“…8F). Next, we used pharmacological approaches by treating day 12 cultured cells with MK-2206 (100 nM), a highly potent and specific inhibitor of AKT activation (Hirai et al 2010;Ji et al 2017). Whereas a high concentration of inhibitors was detrimental to cellular growth, lower concentrations of MK-2206 allowed the generation of human cerebral organoids with morphology and sizes comparable with those of DMSOtreated controls (Fig.…”

Section: Akt-mtor Activation Mediates the Enhanced Npc Proliferation mentioning

confidence: 99%

Cerebral organoid and mouse models reveal a RAB39b–PI3K–mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes

et al. 2020

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Dysregulation of early neurodevelopment is implicated in macrocephaly/autism disorders. However, the mechanism underlying this dysregulation, particularly in human cells, remains poorly understood. Mutations in the small GTPase gene RAB39b are associated with X-linked macrocephaly, autism spectrum disorder (ASD), and intellectual disability. The in vivo roles of RAB39b in the brain remain unknown. We generated Rab39b knockout (KO) mice and found that they exhibited cortical neurogenesis impairment, macrocephaly, and hallmark ASD behaviors, which resembled patient phenotypes. We also produced mutant human cerebral organoids that were substantially enlarged due to the overproliferation and impaired differentiation of neural progenitor cells (NPCs), which resemble neurodevelopmental deficits in KO mice. Mechanistic studies reveal that RAB39b interacts with PI3K components and its deletion promotes PI3K-AKT-mTOR signaling in NPCs of mouse cortex and cerebral organoids. The mTOR activity is robustly enhanced in mutant outer radial glia cells (oRGs), a subtype of NPCs barely detectable in rodents but abundant in human brains. Inhibition of AKT signaling rescued enlarged organoid sizes and NPC overproliferation caused by RAB39b mutations. Therefore, RAB39b mutation promotes PI3K-AKT-mTOR activity and alters cortical neurogenesis, leading to macrocephaly and autistic-like behaviors. Our studies provide new insights into neurodevelopmental dysregulation and common pathways associated with ASD across species.

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Section: Akt-mtor Activation Mediates the Enhanced Npc Proliferation mentioning

confidence: 99%

Cerebral organoid and mouse models reveal a RAB39b–PI3K–mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes

et al. 2020

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“…The cell proliferation was evaluated with MTT assay as described previously [18]. In brief, cells were seeded into 96-well plates at a density of 2×10 3 per well and cultured with DMEM containing 10% FBS.…”

Section: Cell Proliferation Assaymentioning

confidence: 99%

MicroRNA-144-3p Inhibits Tumorigenesis of Oral Squamous Cell Carcinoma by downregulating ERO1L

Jiang

et al. 2020

J. Cancer

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An increasing number of studies indicate that miR-144-3p is dysregulated in numerous cancers, but its role in oral squamous cell carcinoma (OSCC) remains largely unknown. Herein we demonstrated that miR-144-3p expression was significantly downregulated in OSCC tissues and cell lines. Moreover, the low level of miR-144-3p expression was associated with the clinical characteristics of OSCC patients. Furthermore, ectopic expression of miR-144-3p inhibited the proliferation, migration, and invasion of OSCC cells in vitro, and blunted the tumorigenic ability of OSCC cells in vivo. Additionally, the levels of miR-144-3p were negatively correlated with the expression status of endoplasmic reticulum oxidoreduction-1-like (ERO1L) in OSCC cell lines. Subsequently, we identified that ERO1L was a direct target of miR-144-3p. Intriguingly, we found that miR-144-3p downregulation of ERO1L inhibited the activity of signal transducer and activator of transcription 3 (STAT3) in OSCC cells. Therefore, miR-144-3p suppresses tumorigenesis by targeting ERO1L/STAT3 signaling pathway in OSCC. miR-144-3p may a candidate target for OSCC treatment.

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“…Tsc1+/+, Tsc1−/−, Tsc2+/+, Tsc2−/− MEFs, and rat uterine leiomyoma‐derived Tsc2‐null ELT3 cells have been described previously . Human lung cancer cell line, NCI‐H292, and human breast cancer cell line, MDA‐MB‐231, were from the Shanghai Institute of Life Sciences, Chinese Academy of Sciences.…”

Section: Methodsmentioning

confidence: 99%

“…Tsc1+/+, Tsc1−/−, Tsc2+/+, Tsc2−/− MEFs, and rat uterine leiomyoma-derived Tsc2-null ELT3 cells have been described previously. [14][15][16] Human lung cancer cell line, NCI-H292, and human breast cancer cell line, MDA-MB-231, were from the Shanghai Institute of Life Sciences, Chinese Academy of Sciences. Human prostate cancer cell line, PC3, and human embryonic kidney cells (HEK293T) were acquired from American Type Culture Collection (Manassas, VA).…”

Section: Cell Culturementioning

confidence: 99%

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

Wang

Tang

et al. 2020

IUBMB Life

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Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the benign tumor formation in multiple organs. The main etiology of TSC is the loss‐of‐function mutation of TSC1 or TSC2 gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) expression in Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) compared with the control cells. Inhibition of mTORC1 led to a dramatic decrease of PFKFB3 expression, indicating PFKFB3 regulation by mTORC1. Moreover, suppression of mTORC1 inhibited the expression of PFKFB3 in rat uterine leiomyoma‐derived Tsc2‐null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia‐inducible factor 1α (HIF‐1α) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1‐ or Tsc2‐deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1‐ or Tsc2‐null MEFs than treatment with single drug. We conclude that loss of TSC1 or TSC2 led to upregulated expression of PFKFB3 through activation of mTORC1/HIF‐1α signaling pathway and co‐administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1‐related tumors.

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Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex

Cited by 20 publications

References 37 publications

Cerebral organoid and mouse models reveal a RAB39b–PI3K–mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes

Cerebral organoid and mouse models reveal a RAB39b–PI3K–mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes

MicroRNA-144-3p Inhibits Tumorigenesis of Oral Squamous Cell Carcinoma by downregulating ERO1L

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

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