Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance

Johnson, Charlotte E.; Tee, Andrew R.

doi:10.1042/ebc20170056

Cited by 28 publications

(22 citation statements)

References 78 publications

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“…To valid this hypothesis, we treated hFOB 1.19 cells with increasing doses of CNR2 ligands HU308 and JWH133, and found that the autophagic flux was gradually enhanced. mTOR, a serine/threonine protein kinase, is a core component of mTOR complex 1 (mTORC1), the activation of which potently inhibits autophagy [26,27]. Administration of mTOR inhibitor (rapamycin) or genetic ablation of mTOR has been reported to preserve the function of osteoblasts and osteocytes, and prevent bone loss [28,29].…”

Section: Discussionmentioning

confidence: 99%

Activation of cannabinoid receptor type 2-induced osteogenic differentiation involves autophagy induction and p62-mediated Nrf2 deactivation

Yang

Shao

et al. 2020

Cell Commun Signal

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Background: Dysfunction in survival and differentiation of osteoblasts commonly occurs in patients with osteoporosis. Cannabinoid receptor type 2 (CNR2) is a major receptor of endocannabinoid system that is crucial for bone mass homeostasis. Our group prior demonstrated that activation of CNR2 signaling promoted osteogenic differentiation of bone marrow derived mesenchymal stem cells in vitro. Autophagy is reported to participate in osteoblastic differentiation. Whether autophagy is regulated by CNR2-mediated cannabinoid signaling is unknown, and how the autophagy-CNR2 interaction affects osteoblastic differentiation requires further elucidation. Methods: hFOB 1.19 osteoblasts were treated with CNR2 agonists HU308 (5, 10, 25, 50 or 100 nM) and JWH133 (1, 2, 5, 10 or 20 μM) in presence or absence of autophagy inhibitor 3-Methyladenine (3-MA). The differentiation of hFOB 1.19 cells was determined via evaluating their alkaline phosphatase (ALP) activity and mineralization ability (Alizarin red staining). Alterations in autophagy-related molecules and osteogenic markers were analyzed via real-time PCR and/or immunoblotting assays. Results: hFOB 1.19 cells spontaneously differentiated towards mature osteoblasts under 39°C, during which CNR2 expression increased, and autophagy was activated. The strongest autophagy flux was observed at 192 h post differentiation─LC3I to LC3II conversion was enhanced and Beclin 1 expression was upregulated considerably, while p62 expression was downregulated. Treatment of HU308 and JWH133 promoted autophagy in a dose-dependent manner, and suppressed mTOR signaling pathway in hFOB 1.19 cells. In CNR2-silenced cells, HU308's and JWH133's effects on autophagy were weakened. HU308 and JWH133 enhanced the ALP activity and mineralization, and upregulated the expression of osteogenic markers, osteopontin and osteocalcin, in hFOB 1.19 cells. Intriguingly, such pro-osteogenic effects induced by CNR2 activation were markedly mitigated by 3-MA. In addition to provoking autophagy, CNR2 agonists also reduced nuclear Nrf2 accumulation and increased Keap1 expression. Further, reexpression of p62 inhibited CNR2 agonists-induced Nrf2 degradation. Conclusions: Osteogenic differentiation induced by CNR2 signaling activation involves autophagy induction and p62mediated Nrf2 deactivation.

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Section: Discussionmentioning

confidence: 99%

Activation of cannabinoid receptor type 2-induced osteogenic differentiation involves autophagy induction and p62-mediated Nrf2 deactivation

Yang

Shao

et al. 2020

Cell Commun Signal

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“…Even though many water soluble rapalogs were tested in cell and animal models, their effect in the clinic is generally only modest or weak (Kim and Guan, 2019). In some patients, rapalog usage inadvertently promotes cell survival by enhancing the PKB/Akt activity or by activating autophagy which promotes survival in oxygen-deprived microenvironments (Tabernero et al, 2008;Palm et al, 2015;Johnson and Tee, 2017). In some cases, these effects can be countered by combining rapalogs with an autophagy inhibitor hydroxychloroquine (Rangwala et al, 2014).…”

Section: Rapalogsmentioning

confidence: 99%

Transcription and Translation Inhibitors in Cancer Treatment

et al. 2020

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Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

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“…Hypoxia and growth factors can induce the expression of hypoxia inducible factor 1α (HIF-1α) [54] , the downstream blood vessels endothelial growth factor (VEGF) transcription [55] . The PI3K/AKt pathway activation can up-regulate the expression of HIF-1α and VEGF, thus making endothelial cell migrate to form new blood vessels; (2) promoting tumor invasion and metastasis: Johnson and Tee [56] have shown that PI3K/ AKt/mTOR activation can make the downstream molecules p70s6k phosphorylated to make actin filament remodel and to enhance the ability of tumor cells to move, thus increasing the invasion and metastasis of cancer cells. Activation of Akt increases the transcriptional activity of NF-κB and the motor function of tumor cells, which facilitates invasion of cancer cells [57] .…”

Section: Signaling Pathwaysmentioning

confidence: 99%

Understanding the inflammation-cancer transformation in the development of primary liver cancer

Chen¹,

Hu²,

Xu³

et al. 2018

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Primary liver cancer is one of the leading causes of cancer-related deaths worldwide. China has more than 55% liver cancer cases globally. The development of hepatocellular carcinoma (HCC) was caused by a variety of risks factors, including chronic inflammation by virus, alcohol consumption and non-alcoholic steatohepatitis. Emerging evidence has notarized inflammation as a critical component of HCC progression. The development of HCC is a multistep process which may originate from liver chronic injury and inflammation to subsequent fibrosis and/or cirrhosis and finally HCC. A large number of studies indicate that chemokines and cytokines are candidates linking molecules between inflammation and liver cancer. Here, we will describe a few of the key cytokines and chemokines and signal pathways which are involved in the inflammation of HCC. Inhibitors of inflammation for the prevention and overcoming antitumor immunity for treatment of liver cancer are promising candidates for the future management of patients with HCC.

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Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance

Cited by 28 publications

References 78 publications

Activation of cannabinoid receptor type 2-induced osteogenic differentiation involves autophagy induction and p62-mediated Nrf2 deactivation

Activation of cannabinoid receptor type 2-induced osteogenic differentiation involves autophagy induction and p62-mediated Nrf2 deactivation

Transcription and Translation Inhibitors in Cancer Treatment

Understanding the inflammation-cancer transformation in the development of primary liver cancer

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