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PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

ABSTRACT: The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

SUBMITTER: Glaviano A

PROVIDER: S-EPMC10436543 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

Glaviano Antonino A Foo Aaron S C ASC Lam Hiu Y HY Yap Kenneth C H KCH Jacot William W Jones Robert H RH Eng Huiyan H Nair Madhumathy G MG Makvandi Pooyan P Geoerger Birgit B Kulke Matthew H MH Baird Richard D RD Prabhu Jyothi S JS Carbone Daniela D Pecoraro Camilla C Teh Daniel B L DBL Sethi Gautam G Cavalieri Vincenzo V Lin Kevin H KH Javidi-Sharifi Nathalie R NR Toska Eneda E Davids Matthew S MS Brown Jennifer R JR Diana Patrizia P Stebbing Justin J Fruman David A DA Kumar Alan P AP

Molecular cancer 20230818 1

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and ...[more]

PMID: 37596643

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Project description:Gynostemma pentaphyllum (Thunb.) Makino (G. pentaphyllum) is a natural herbal drug that has been widely used to treat many diseases. The antitumor effects of G. pentaphyllum were first described in the illustrated catalog of plants. Gypenosides are the major active components of G. pentaphyllum, and they have been widely reported to possess antitumor effects in prostate cancer, gastric cancer, hepatocellular carcinoma, colon cancer, lung cancer, and breast cancer. However, research on the use of gypenoside in the treatment of bladder cancer has not been conducted. In this study, we explored the potential molecular mechanisms of gypenosides in the treatment of bladder cancer using network pharmacology and experimental validation. First, we used a network pharmacology-based method to identify both the effective components of gypenosides and the molecular mechanism underlying their antibladder cancer effects. The results were further confirmed by molecular docking, CCK8 and colony formation assays, and cell cycle and cell apoptosis analyses. Additionally, a mouse xenograft model of bladder cancer was used to investigate the antitumor effect of gypenosides in vivo. We identified 10 bioactive ingredients and 163 gene targets of gypenosides. Network exploration suggested that VEGFA, STAT3, and PI3KCA may be candidate agents for the antibladder cancer effect of gypenosides. In addition, analysis of the Kyoto Encyclopedia of Genes and Genomes pathway revealed that the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway may play a crucial role in the mechanism of action of gypenosides against bladder cancer. Molecular docking revealed that gypenosides combine well with PI3K, AKT, and mTOR. As expected, gypenosides displayed apoptosis-inducing properties in bladder cancer cells by inactivating the PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, gypenosides significantly (P < 0.05) inhibited the growth of bladder cancer cells in vivo. Mechanistically, gypenosides induced the apoptosis of bladder cancer cells via inactivation of the PI3K/AKT/mTOR signaling pathway.

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PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

Publications

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

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