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Cells
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PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0
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PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: 15 November 2024 | Viewed by 10885

Special Issue Editors

Dr. Jean Christopher Chamcheu

E-Mail Website
Guest Editor
Department of Biological Sciences and Chemistry, College of Sciences and Engineering, Southern University and A&M College, Baton Rouge, LA 70807, USA
Interests: skin health and diseases; carcinogenesis; inflammation; dermatology; psoriasis; atopic dermatitis; bioactive natural products; antioxidants; polyphenols; flavonoids; tissue engineering; signaling pathways; pharmacology
Special Issues, Collections and Topics in MDPI journals
Dr. Claudia Bürger

E-Mail Website
Guest Editor
Academy for Educational Research and Teacher Training, Goethe University Frankfurt, 60629 Frankfurt am Main, Germany
Interests: mTOR; inflammation; tissue engineering; dermatology
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Shile Huang

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA
Interests: mTOR; cell signaling; cell motility; natural products; cadmium
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This is the second edition of PI3K/AKT/mTOR Signaling Network in Human Health and Diseases (https://www.mdpi.com/journal/cells/special_issues/PI3K_AKT_mTOR) that 1st edition resulted in publishing of 15 papers.

The phosphatidylinositiol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in regulating cell growth, proliferation, survival, motility, differentiation, angiogenesis, and metabolism. Over the last two decades, there have been major strides in our molecular understanding of the role of PI3K/AKT/mTOR signaling in physiological processes, and we have discovered the complexity of the events mediated by this network, with the highly conserved mTOR complex (mTORC) as a central point of integration. In addition, increasing evidence suggests that PI3K/AKT/mTOR signaling is frequently dysregulated in diverse human pathologies, including malignant, neurodegenerative, autoimmune, cardiovascular, and metabolic diseases. Thus, therapeutic strategies with different rationales have been explored that target components of this signaling axis as well as associated pathways that benefit patients in various clinical settings.

Rapalogs (e.g., Temsirolimus and Everolimus), which are the first generation mTOR inhibitors (mTORC1 inhibitors), have been used to treat advanced renal carcinoma and other tumors. Recently, the second generation mTOR inhibitors, called TOR kinase inhibitors (TORKIs), which compete with ATP within the catalytic site of mTOR and inhibit both mTORC1 and mTORC2, have been under preclinical and clinical evaluation. These TORKIs are more potent than rapalogs in various preclinical cancer models but show severe adverse effects in patients. In addition, several AKT and PI3K inhibitors have also been developed. In combination with PI3K or mTOR inhibitors, AKT inhibitors have shown promising preclinical results in several malignancies and other diseases. However, none of them have been approved by the U.S. FDA for treating human diseases.

Therefore, there is a dire need to advance the investigation of PI3K/AKT/mTOR signaling in human pathologies to develop novel therapies with high efficacy and low toxicity. This Special Issue, entitled “The PI3K/AKT/mTOR Signaling Network in Human Health and Diseases” aims to present a collection of articles related to the PI3K/AKT/mTOR signaling pathway in human health and diseases, including but not limited to cancer, ageing, neurodegenerative disorders, inflammation, autoimmune diseases, obesity, and diabetes. The emphasis will be on the molecular facets of PI3K/AKT/mTOR in specific diseases. Original research (preclinical and clinical) and review articles are welcome.

Dr. Jean Christopher Chamcheu
Dr. Claudia Bürger
Prof. Dr. Shile Huang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acne
  • ageing
  • Akt
  • Alzheimer’s disease
  • autophagy
  • autoimmunity
  • PI3K
  • mTOR
  • cancer
  • cardiovascular diseases
  • diabetes
  • growth
  • hamartoma
  • hypertrophy
  • inflammation
  • neurologic
  • tuberous sclerosis
  • systemic sclerosis
  • obesity
  • Parkinson’s disease
  • psoriasis
  • atopic dermatitis
  • burns/wound healing
  • targeted therapy
  • natural products
  • biologics

Published Papers (6 papers)

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Research

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15 pages, 3378 KiB  
Article
Metabolic Disruption Induced by mTOR Signaling Pathway Inhibition in Regulatory T-Cell Expansion for Clinical Application
by Roberto Gedaly, Gabriel Orozco, Alexandre P. Ancheta, Mackenzie Donoho, Siddharth N. Desai, Fanny Chapelin, Aman Khurana, Lillie J. Lewis, Cuiping Zhang and Francesc Marti
Cells 2023, 12(16), 2066; https://doi.org/10.3390/cells12162066 - 15 Aug 2023
Viewed by 1534
Abstract
Background: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess the efficacy of [...] Read more.
Background: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess the efficacy of the mTORC1/C2 inhibitor, AZD8055, in the manufacturing of clinically competent Treg cells and compare the effects with those induced by rapamycin (RAPA), another mTOR inhibitor commonly used in Treg expansion protocols. Methods: Primary human Treg cells were isolated from leukapheresis product. Cell viability, expansion rates, suppressive function, autophagy, mitochondrial unfolded protein response (mitoUPR), and cell metabolic profile were assessed. Results: We observed a stronger inhibition of the mTORC2 signaling pathway and downstream events triggered by Interleukin 2 (IL2)-receptor in AZD8055-treated cells compared with those treated with RAPA. AZD8055 induced progressive metabolic changes in mitochondrial respiration and glycolytic pathways that disrupted the long-term expansion and suppressive function of Tregs. Unlike RAPA, AZD8055 treatment impaired autophagy and enhanced the mitoUPR cell stress response pathway. Conclusions: A distinct pattern of mTOR inhibition by AZD, compared with RAPA, induced mitochondrial stress response and dysfunction, impaired autophagy, and disrupted cellular bioenergetics, resulting in the loss of proliferative potential and suppressive function of Treg cells. Full article
(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0)
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15 pages, 3903 KiB  
Article
FNBP1 Facilitates Cervical Cancer Cell Survival by the Constitutive Activation of FAK/PI3K/AKT/mTOR Signaling
by Jun Zhang, Xin Li, Yunfei Zhou, Mingming Lin, Qianying Zhang and Yunhong Wang
Cells 2023, 12(15), 1964; https://doi.org/10.3390/cells12151964 - 29 Jul 2023
Viewed by 1145
Abstract
Cervical cancer is the most prevalent gynecological tumor among women worldwide. Although the incidence and mortality of cervical cancer have been declining thanks to the wide-scale implementation of cytological screening, it remains a major challenge in clinical treatment. High viability is one of [...] Read more.
Cervical cancer is the most prevalent gynecological tumor among women worldwide. Although the incidence and mortality of cervical cancer have been declining thanks to the wide-scale implementation of cytological screening, it remains a major challenge in clinical treatment. High viability is one of the leading causes of the chemotherapeutic resistance in cervical cancers. Formin-binding protein 1 (FNBP1) could stimulate F-actin polymerization beneath the curved plasma membrane in the cell migration and endocytosis, which had previously been well defined. Here, FNBP1 was also demonstrated to play a crucial role in cervical cancer cell survival, and the knockdown of which could result in the attenuation of FAK/PI3K/AKT signaling followed by significant apoptotic accumulation and proliferative inhibition. In addition, the epidermal growth factor (hrEGF) abrogated all the biological effects mediated by the silencing of FNBP1 except for the cell adhesion decrease. These findings indicated that FNBP1 plays a key role in maintaining the activity of focal adhesion kinase (FAK) by promoting cell adhesion. The activated FAK positively regulated downstream PI3K/AKT/mTOR signaling, which is responsible for cell survival. Promisingly, FNBP1 might be a potential target against cervical cancer in combination therapy. Full article
(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0)
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Review

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28 pages, 4808 KiB  
Review
CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance
by Naji Kharouf, Thomas W. Flanagan, Abdulhadi A. Alamodi, Youssef Al Hmada, Sofie-Yasmin Hassan, Hosam Shalaby, Simeon Santourlidis, Sarah-Lilly Hassan, Youssef Haikel, Mossad Megahed, Robert T. Brodell and Mohamed Hassan
Cells 2024, 13(3), 240; https://doi.org/10.3390/cells13030240 - 26 Jan 2024
Viewed by 1141
Abstract
Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials [...] Read more.
Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed. Full article
(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0)
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17 pages, 2843 KiB  
Review
Autophagy and Apoptosis in Rabies Virus Replication
by Saisai Li, Bowen Xu, Yongwen Luo, Jun Luo, Shile Huang and Xiaofeng Guo
Cells 2024, 13(2), 183; https://doi.org/10.3390/cells13020183 - 18 Jan 2024
Viewed by 1571
Abstract
Rabies virus (RABV) is a single-stranded negative-sense RNA virus belonging to the Rhabdoviridae family and Lyssavirus genus, which is highly neurotropic and can infect almost all warm-blooded animals, including humans. Autophagy and apoptosis are two evolutionarily conserved and genetically regulated processes that maintain [...] Read more.
Rabies virus (RABV) is a single-stranded negative-sense RNA virus belonging to the Rhabdoviridae family and Lyssavirus genus, which is highly neurotropic and can infect almost all warm-blooded animals, including humans. Autophagy and apoptosis are two evolutionarily conserved and genetically regulated processes that maintain cellular and organismal homeostasis, respectively. Autophagy recycles unnecessary or dysfunctional intracellular organelles and molecules in a cell, whereas apoptosis eliminates damaged or unwanted cells in an organism. Studies have shown that RABV can induce both autophagy and apoptosis in target cells. To advance our understanding of pathogenesis of rabies, this paper reviews the molecular mechanisms of autophagy and apoptosis induced by RABV and the effects of the two cellular events on RABV replication. Full article
(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0)
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13 pages, 1332 KiB  
Review
Effects of Everolimus in Modulating the Host Immune Responses against Mycobacterium tuberculosis Infection
by Anmol Raien, Sofia Davis, Michelle Zhang, David Zitser, Michelle Lin, Graysen Pitcher, Krishna Bhalodia, Selvakumar Subbian and Vishwanath Venketaraman
Cells 2023, 12(22), 2653; https://doi.org/10.3390/cells12222653 - 18 Nov 2023
Viewed by 1259
Abstract
The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (P13K/AKT/mTOR) pathway plays a key role in tuberculosis (TB) pathogenesis and infection. While the activity levels of this pathway during active infection are still debated, manipulating this pathway shows potential benefit for host-directed therapies. Some [...] Read more.
The phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (P13K/AKT/mTOR) pathway plays a key role in tuberculosis (TB) pathogenesis and infection. While the activity levels of this pathway during active infection are still debated, manipulating this pathway shows potential benefit for host-directed therapies. Some studies indicate that pathway inhibitors may have potential for TB treatment through upregulation of autophagy, while other studies do not encourage the use of these inhibitors due to possible host tissue destruction by Mycobacterium tuberculosis (M. tb) and increased infection risk. Investigating further clinical trials and their use of pathway inhibitors is necessary in order to ascertain their potential for TB treatment. This paper is particularly focused on the drug everolimus, an mTOR inhibitor. One of the first clinical trials sponsored by the Aurum Institute showed potential benefit in using everolimus as an adjunctive therapy for tuberculosis. Infection with tuberculosis is associated with a metabolic shift from oxidative phosphorylation towards glycolysis. The everolimus arm in the clinical trial showed further reduction than the control for both maximal and peak glycolytic activity. Compared with control, those receiving everolimus demonstrated increased lung function through forced expiratory volume in 1 s (FEV1) measurements, suggesting that everolimus may mitigate inflammation contributing to lung damage. Full article
(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0)
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66 pages, 15717 KiB  
Review
The PI3K-Akt-mTOR and Associated Signaling Pathways as Molecular Drivers of Immune-Mediated Inflammatory Skin Diseases: Update on Therapeutic Strategy Using Natural and Synthetic Compounds
by Tithi Roy, Samuel T. Boateng, Mohammad B. Uddin, Sergette Banang-Mbeumi, Rajesh K. Yadav, Chelsea R. Bock, Joy T. Folahan, Xavier Siwe-Noundou, Anthony L. Walker, Judy A. King, Claudia Buerger, Shile Huang and Jean Christopher Chamcheu
Cells 2023, 12(12), 1671; https://doi.org/10.3390/cells12121671 - 20 Jun 2023
Cited by 9 | Viewed by 3473
Abstract
The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of [...] Read more.
The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders. Full article
(This article belongs to the Special Issue PI3K/AKT/mTOR Signaling Network in Human Health and Diseases 2.0)
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