Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression

Qin, Senlin; Wang, Guoyan; Chen, Lei; Geng, Huijun; Zheng, Yining; Xia, Chao; Wu, Shengru; Yao, Junhu; Deng, Lu

doi:10.1371/journal.pgen.1010629

Cited by 9 publications

(6 citation statements)

References 61 publications

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“…In line with this notion, enhanced AKT activation in vivo promoted the retention of embryonic RG cells in the V‐SVZ, and in vitro, promoted a stem cell state (Sinor & Lillien, 2004). Although in this work we did not elucidate which effectors upstream of AKT are modulated by AA and/or SVCT2, other authors have established that AA down‐regulated IGF‐1R as well as the activity of PI3K/AKT, MAPK/ERK, and mTOR signaling (Lee et al, 2008; Qin et al, 2023; Su et al, 2019). Therefore, it is likely that when we overexpressed SVCT2 in the lRG cells in vivo, mTORC2 and PDK1 were inactivated and unable to phosphorylate AKT, and therefore GSK3‐β is activated, thus promoting the generation of migratory neurons.…”

Section: Discussionmentioning

confidence: 77%

Ascorbic acid and its transporterSVCT2, affect radial glia cells differentiation in postnatal stages

Saldivia,

Salazar,

Cifuentes

et al. 2024

Glia

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Radial glia (RG) cells generate neurons and glial cells that make up the cerebral cortex. Both in rodents and humans, these stem cells remain for a specific time after birth, named late radial glia (lRG). The knowledge of lRG and molecules that may be involved in their differentiation is based on very limited data. We analyzed whether ascorbic acid (AA) and its transporter SVCT2, are involved in lRG cells differentiation. We demonstrated that lRG cells are highly present between the first and fourth postnatal days. Anatomical characterization of lRG cells, revealed that lRG cells maintained their bipolar morphology and stem‐like character. When lRG cells were labeled with adenovirus‐eGFP at 1 postnatal day, we detected that some cells display an obvious migratory neuronal phenotype, suggesting that lRG cells continue generating neurons postnatally. Moreover, we demonstrated that SVCT2 was apically polarized in lRG cells. In vitro studies using the transgenic mice SVCT2+/− and SVCT2tg (SVCT2‐overexpressing mouse), showed that decreased SVCT2 levels led to accelerated differentiation into astrocytes, whereas both AA treatment and elevated SVCT2 expression maintain the lRG cells in an undifferentiated state. In vivo overexpression of SVCT2 in lRG cells generated cells with a rounded morphology that were migratory and positive for proliferation and neuronal markers. We also examined mediators that can be involved in AA/SVCT2‐modulated signaling pathways, determining that GSK3‐β through AKT, mTORC2, and PDK1 is active in brains with high levels of SVCT2/AA. Our data provide new insights into the role of AA and SVCT2 in late RG cells.

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Section: Discussionmentioning

confidence: 77%

Ascorbic acid and its transporterSVCT2, affect radial glia cells differentiation in postnatal stages

Saldivia,

Salazar,

Cifuentes

et al. 2024

Glia

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“…Nonetheless, it is noteworthy that mTORC2 activity is profoundly affected by multiple metabolic intermediates. 35,36 Therefore, mTORC2 activity and its regulated cellular metabolic pathways could a reciprocal signaling network distinct cancer types, which requires in-depth examination in the future.…”

Section: Discussionmentioning

confidence: 99%

mTORC2‐AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells

Li,

Wu,

Pan

et al. 2024

The FASEB Journal

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Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem cells and cancer, its regulatory mechanisms are still being updated. Here, we found a previously unappreciated mechanism of mammalian target of rapamycin complex 2 (mTORC2) in regulating glycolysis in intestinal stem cell maintenance and cancer progression. mTORC2 key subunits expression levels and its kinase activity were specifically upregulated in intestinal stem cells, mouse intestinal tumors, and human colorectal cancer (CRC) tissues. Genetic ablation of its key scaffolding protein Rictor in both mouse models and cell lines revealed that mTORC2 played an important role in promoting intestinal stem cell proliferation and self‐renewal. Moreover, utilizing mouse models and organoid culture, mTORC2 loss of function was shown to impair growth of gut adenoma and tumor organoids. Based on these findings, we performed RNA‐seq and noticed significant metabolic reprogramming in Rictor conditional knockout mice. Among all the pathways, carbohydrate metabolism was most profoundly altered, and further studies demonstrated that mTORC2 promoted glycolysis in intestinal epithelial cells. Most importantly, we showed that a rate‐limiting enzyme in regulating glycolysis, 6‐phosphofructo‐2‐kinase (PFKFB2), was a direct target for the mTORC2‐AKT signaling. PFKFB2 was phosphorylated upon mTORC2 activation, but not mTORC1, and this process was AKT‐dependent. Together, this study has identified a novel mechanism underlying mTORC2 activated glycolysis, offering potential therapeutic targets for treating CRC.

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“…These findings imply a feedback loop such that as mTORC2 activity is elevated, rictor ubiquitination is suppressed. The FBXW7-mediated degradation of rictor is also promoted by pharmacological Vitamin C (VitC) treatment of cancer cells [ 119 ]. VitC induces intracellular reactive oxygen species (ROS), which enhance the GSK3/FBXW7-mediated rictor ubiquitination, leading to the death of cancer cells.…”

Section: Post-translational Modification Of Mtorc2 Componentsmentioning

confidence: 99%

The mTORC2 signaling network: targets and cross-talks

Ragupathi,

Kim,

Jacinto

2024

Biochemical Journal

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The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.

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Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression

Cited by 9 publications

References 61 publications

Ascorbic acid and its transporterSVCT2, affect radial glia cells differentiation in postnatal stages

Ascorbic acid and its transporterSVCT2, affect radial glia cells differentiation in postnatal stages

mTORC2‐AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells

The mTORC2 signaling network: targets and cross-talks

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