Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis

Hu, Zhongdong; Wang, Ying; Huang, Fuqiang; Chen, Rongrong; Li, Chunjia; Wang, Fang; Goto, June; Kwiatkowski, David J.; Wdzieczak‐Bakala, Joanna; Tu, Pengfei; Liu, Jian‐Miao; Zha, Xiaojun; Zhang, Hongbing

doi:10.1074/jbc.m115.665208

Cited by 37 publications

(35 citation statements)

References 49 publications

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“…These reports demonstrate the critical role of BEX2 in regulating autophagy, which is of particular importance in the present study where BEX2 was associated with isoflavone-mediated autophagic flux in dopaminergic cells. Moreover, BEX2 levels were reduced in the presence of rapamycin to inhibit mTOR, supporting previous reports that mTOR positively regulates BEX2 expression [46]. Further investigation is needed to identify other signaling pathways involved in isoflavone-mediated autophagy induction and BEX2 expression.…”

Section: Discussionsupporting

confidence: 83%

Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells

Ma¹,

Wu²,

Wu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Atrazine (ATR) is a broad-spectrum herbicide in wide use around the world. However, ATR is neurotoxic and can cause cell death in dopaminergic neurons, leading to neurodegenerative disorders. Autophagy is the basic cellular catabolic process involving the degradation of proteins and damaged organelles. Studies have shown that certain plant compounds can induce autophagy and prevent neuronal cell death. This prompted us to investigate plant compounds that might reduce the neurotoxic effects of ATR. Methods: By CCK-8 and flow cytometry, we tested the ability of five candidate compounds—isoflavones, resveratrol, quercetin, curcumin, and green tea polyphenols—to protect cells from ATR. Changes in the expression of tyrosine hydroxylase (TH) and brain-expressed X-linked 2 (BEX2), autophagy-related proteins and key factors in mTOR signaling, were detected by Western blotting. Results: Isoflavones had the strongest activity against ATR-induced neuronal apoptosis. ATR reduced the expression of TH and BEX2, whereas isoflavones increased TH and BEX2 expression. In addition, ATR inhibited autophagy, whereas isoflavones induced autophagy through the accumulation of LC3-II and decreased expression of p62; this effect was abolished by 3-methyladenine (3-MA). Furthermore, BEX2 siRNA abolished isoflavone-mediated autophagy and neuroprotection in vitro. Conclusion: Isoflavones activate BEX2-dependent autophagy, protecting against ATR-induced neuronal apoptosis.

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Section: Discussionsupporting

confidence: 83%

Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells

Ma¹,

Wu²,

Wu³

et al. 2017

Cell Physiol Biochem

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“…The signaling relationship between mTOR and STAT3 has been suggested in a few studies regarding mTOR inhibitor development (26)(27)(28). Specifically, Hu et al (27) identified brain-expressed X-linked 2 (BEX2), a novel downstream molecule of the mTOR pathway; they found that mTOR signal activation can be mediated by BEX2 and transmitted to the STAT3 and NF-ĸB pathways.…”

Section: Inhibitory Effect Of Stx-0119 And/or Rapamycin On In Vivo mentioning

confidence: 99%

“…Specifically, Hu et al (27) identified brain-expressed X-linked 2 (BEX2), a novel downstream molecule of the mTOR pathway; they found that mTOR signal activation can be mediated by BEX2 and transmitted to the STAT3 and NF-ĸB pathways. Oroxylin, a natural monoflavonoid, reported by Zou et al, inhibited Akt and ERK activation and the downstream phosphorylation of mTOR and STAT3, which was mediated by Beclin 1, a key autophagyrelated protein (28).…”

Section: Inhibitory Effect Of Stx-0119 And/or Rapamycin On In Vivo mentioning

confidence: 99%

Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide-resistant Glioblastoma Cell Line

Miyata

Ashizawa

Iizuka

et al. 2017

CGP

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Abstract. Background: Temozolomide-resistant (TMZ-R) glioblastoma is very difficult to treat, and a novel approach toGlioblastoma (GB) is one of the most malignant and aggressive tumors and has a very poor prognosis, with a mean survival time of less than 2 years even with the recent development of temozolomide (TMZ)-based intensive treatment (1, 2). Once recurrence develops, there are few therapeutic approaches to control the growth of glioblastoma. Therefore, TMZ-resistant GB is very difficult to treat, and a novel approach to overcome resistance is needed.With regard to the mechanism of TMZ resistance, O 6 -methylguanine-DNA -methyltransferase (MGMT) removes methylation from the O 6 position of guanine and contributes to TMZ resistance induction (3). It is generally accepted that high MGMT expression through the methylation of the MGMT promoter is one of the mechanisms responsible for TMZ resistance. Alternatively, several novel biomarkers linked to MGMT expression and the methylation status such as the HOX signature and epidermal growth factor receptor (EGFR) expression (4), somatic mutation of mismatch repair gene mutS homolog (MSH)6 (5), prolyl 4-hydroxylase, beta polypeptide (P4HB), EGFR mutation (EGFRvIII) (6), CD74 and signal transducer and activator of transcription (STAT)3 signaling have been reported. Kohsaka et al. reported the association of STAT3 expression with MGMT expression level using small interfering (si)RNA-mediated STAT3 gene inhibition (7).Additionally, mammalian target of rapamycin (mTOR) signaling is activated in TMZ-resistant glioma cells as a result of EGFR, phosphoinositide 3 kinase (PI3K) and Akt signaling activation. mTOR is a Ser/Thr kinase that belongs to the phosphoinositide kinase-related family of protein kinases (PIKKs). mTOR acts as an essential integrator of growth-factor-activated and nutrient-sensing pathways to control and coordinate various cellular functions, including survival, proliferation, differentiation, autophagy and metabolism (8)(9)(10)(11) This article is freely accessible online. *These authors contributed equally to this study.Abbreviations: GB: Glioblastoma, TMZ: temozolomide, MGMT: O 6 -methylguanine-O 6 -methylguanine-DNAmethyltransferase, STAT: signal transducer and activator of transcription, mTOR: mammalian target of rapamycin, shRNA: small hairpin RNA.

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“…Total cellular protein was extracted using RIPA lysate (Beyotime Biotechnology, Haimen, China). The protein expression was analyzed by western blot as previously described . In brief, lysates from the cell or tissue were separated by NuPAGE 4–12% Bis‐Tris and then were transferred to the PVDF membrane (Millipore).…”

Section: Methodsmentioning

confidence: 99%

“…The protein expression was analyzed by western blot as previously described. 17 In brief, lysates from the cell or tissue were separated by NuPAGE 4-12% Bis-Tris and then were transferred to the PVDF membrane (Millipore). After blocked with the 5% nonfat milk (BBI Life Sciences, Shanghai, China), the bands were incubated with the primary antibodies.…”

Section: Western Blotmentioning

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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Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis

Cited by 37 publications

References 49 publications

Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells

Isoflavones Induce BEX2-Dependent Autophagy to Prevent ATR-Induced Neurotoxicity in SH-SY5Y Cells

Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide-resistant Glioblastoma Cell Line

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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