The Orexin-A-Regulated Akt/mTOR Pathway Promotes Cell Proliferation Through Inhibiting Apoptosis in Pancreatic Cancer Cells

Suo, Linna; Chang, Xin; Yang, Zhao

doi:10.3389/fendo.2018.00647

Cited by 23 publications

(20 citation statements)

References 40 publications

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“…Data are also contrasting for pancreatic ductal cancer and prostate carcinoma. One study reported that OR1 signaling promotes cell proliferation in pancreatic ductal cancer cells [ 133 ], whereas another study indicated that both agonism (OXA) and antagonism (almorexant) of OR1 exert an antitumoral proapoptotic effect on pancreatic ductal cancer in vitro and in vivo [ 134 ]. On the other hand, OR1 was found to be overexpressed and to mediate apoptosis in advanced prostate cancer with a neuroendocrine differentiation [ 135 ].…”

Section: Orexin Cancer and Neurodegenerative Diseasesmentioning

confidence: 99%

Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

Mogavero

Silvani

DelRosso

et al. 2021

Cancers

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Conditions such as Alzheimer’s (AD) and Parkinson’s diseases (PD) are less prevalent in cancer survivors and, overall, cancer is less prevalent in subjects with these neurodegenerative disorders. This seems to suggest that a propensity towards one type of disease may decrease the risk of the other. In addition to epidemiologic data, there is also evidence of a complex biological interconnection, with genes, proteins, and pathways often showing opposite dysregulation in cancer and neurodegenerative diseases. In this narrative review, we focus on the possible role played by orexin signaling, which is altered in patients with narcolepsy type 1 and in those with AD and PD, and which has been linked to β-amyloid brain levels and inflammation in mouse models and to cancer in cell lines. Taken together, these lines of evidence depict a possible case of inverse comorbidity between cancer and neurodegenerative disorders, with a role played by orexins. These considerations suggest a therapeutic potential of orexin modulation in diverse pathologies such as narcolepsy, neurodegenerative disorders, and cancer.

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Section: Orexin Cancer and Neurodegenerative Diseasesmentioning

confidence: 99%

Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

Mogavero

Silvani

DelRosso

et al. 2021

Cancers

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“…Кроме того, обработка орексином А предотвращает апоптоз клеткок PANC1, тогда как ингибирование OX1R приводит к апоптозу путем регулирования уровней экспрессии в клетках проапоптотических белков Bcl-2, каспазы-9 и c-myc. Авторы считают, что стимуляция рецептора OX1R может быть важна для регуляции онкогенеза при раке поджелудочной железы и является потенциальной мишенью для лечения пациентов с данным типом рака [49].…”

Section: орексин и апоптоз опухолевых клетокunclassified

Tumor cell apoptosis mediated by the orexins

et al. 2021

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Orexins A and B are neuropeptides synthesized by a population of lateral hypothalamic neurons. Orexin’s physiological function consists mainly in regulating the sleep-wake cycle, eating behavior, and energy homeostasis. Axons of orexin-containing neurons are projected onto many structures of brain and spinal cord, thus providing a variety of their physiological effects. Moreover, the components of the orexinergic system are identified in various peripheral organs and tissues. The effects of orexins are mediated via two receptors (OX1R and OX2R) coupled with G-proteins (GPCRs). The classical signal transmission pathway through orexin receptors in neuronal cells includes an increase of the intracellular calcium as a result of the opening of TRPC membrane channels and IP3 endoplasmic reticulum (ER) channels. In addition to the classic orexin receptors signaling, there is an alternative pathway. Signal transmission through the alternative pathway leads to apoptosis of tumor cells. This pathway is probably due to the structural feature of orexin receptors compared to other GPCRs — the presence of a tyrosine-based immunoreceptor inhibition motif (ITIM). Such motifs are not limited to GPCRs, but are a hallmark of immuno-inhibiting receptors on lymphoid and myeloid cells. ITIM recruits either SHP1 and SHP2 protein tyrosine phosphatases or SHIP1 and SHIP2 inositol phosphatases, to mediate negative signal transduction. A further mechanism of the so-called orexin-induced apoptosis seems to include the p38/MAPK phosphorylation and the cytochrome c releasing from mitochondria, followed by activation of caspases 3 and 7 and cell death. It should be emphasized that this alternative pathway is present only in certain types of tumor cells. This review summarizes the available data on orexin-induced apoptosis of tumor cells from intestines, pancreas, stomach, prostate, endometrium, adrenal glands and glia, and also considers possible mechanisms for its implementation.

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“…Importantly, the AKT/ mammalian target of rapamycin (mTOR) is known as one of the most critical pathways in regulating cell development, proliferation, and survival [16]. A further study has indicated that the activation of the AKT/mTOR pathway could enhance cell proliferation in PC cells [17]. Besides, another study suggested that the AKT/mTOR pathway could also impact the survival ability and proliferation of prostate cancer cells [18].…”

Section: Introductionmentioning

confidence: 99%

Silencing of microRNA-135b inhibits invasion, migration, and stemness of CD24+CD44+ pancreatic cancer stem cells through JADE-1-dependent AKT/mTOR pathway

et al. 2020

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Background: Recent studies have emphasized determining the ability of microRNAs (miRNAs) as crucial regulators in the occurrence and development of pancreatic cancer (PC), which continues to be one of the deadliest malignancies with few effective therapies. The study aimed to investigate the functional role of miR-135b and its associated mechanism to unravel the biological characteristics of tumor growth in pancreatic cancer stem cells (PCSCs). Methods: Microarray analyses were initially performed to identify the PC-related miRNAs and genes. The expression of miR-135b and PCSC markers in PC tissues and cells was determined by RT-qPCR and western blot analysis, respectively. The potential gene (JADE-1) that could bind to miR-135b was confirmed by the dual-luciferase reporter assay. To investigate the tumorigenicity, migration, invasion, and stemness of PC cells, several gain-of-function and loss-offunction genetic experiments were conducted. Finally, tumor formation in nude mice was conducted to confirm the results in vivo. Results: miR-135b was highly-expressed in PC tissues and PCSCs, which was identified to specifically target JADE-1. The overexpression of miR-135b promoted proliferation, migration, and invasion of PCSC, inhibited cell apoptosis and increased the expression of stemness-related factors (Sox-2, Oct-4, Nanog, Aldh1, and Slug). Moreover, miR-135b could promote the expression of phosphorylated AKT and phosphorylated mTOR in the AKT/mTOR pathway. Additionally, miR-135b overexpression accelerated tumor growth in nude mice. Conclusions: Taken together, the silencing of miR-135b promotes the JADE-1 expression, which inactivates the AKT/mTOR pathway and ultimately results in inhibition of self-renewal and tumor growth of PCSCs. Hence, this study contributes to understanding the role of miR-135 in PCSCs and its underlying molecular mechanisms to aid in the development of effective PC therapeutics.

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The Orexin-A-Regulated Akt/mTOR Pathway Promotes Cell Proliferation Through Inhibiting Apoptosis in Pancreatic Cancer Cells

Cited by 23 publications

References 40 publications

Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

Tumor cell apoptosis mediated by the orexins

Silencing of microRNA-135b inhibits invasion, migration, and stemness of CD24+CD44+ pancreatic cancer stem cells through JADE-1-dependent AKT/mTOR pathway

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