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      Natural bioactive compounds and FOXO3a in cancer therapeutics: An update.

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          Abstract

          Forkhead box protein 3a (FOXO3a) is a transcription factor that regulates various downstream targets upon its activation, leading to the upregulation of tumor suppressor and apoptotic pathways. Hence, targeting FOXO3a is an emerging strategy for cancer prevention and treatment. Recently, Natural Bioactive Compounds (NBCs) have been used in drug discovery for treating various disorders including cancer. Notably, several NBCs have been shown as potent FOXO3a activators. NBCs upregulate FOXO3a expressions through PI3K/Akt, MEK/ERK, AMPK, and IκB signaling pathways. FOXO3a promotes its anticancer effects by upregulating the levels of its downstream targets, including Bim, FasL, and Bax, leading to apoptosis. This review focuses on the dysregulation of FOXO3a in carcinogenesis and explores the potent FOXO3a activating NBCs for cancer prevention and treatment. Additionally, the review evaluates the safety and efficacy of NBCs. Looking ahead, NBCs are anticipated to become a cost-effective, potent, and safer therapeutic option for cancer, making them a focal point of research in the field of cancer prevention and treatment.

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          Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.

          Anne Brunet, Azad Bonni, Michael Zigmond … (1999)
          Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/ threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
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            FoxO transcription factors; Regulation by AKT and 14-3-3 proteins.

            Guri Tzivion, Melissa Dobson, Gopalakrishnan Ramakrishnan (2011)
            The forkhead box O (FoxO) transcription factor family is a key player in an evolutionary conserved pathway downstream of insulin and insulin-like growth factor receptors. The mammalian FoxO family consists of FoxO1, 3, 4 and 6, which share high similarity in their structure, function and regulation. FoxO proteins are involved in diverse cellular and physiological processes including cell proliferation, apoptosis, reactive oxygen species (ROS) response, longevity, cancer and regulation of cell cycle and metabolism. The regulation of FoxO protein function involves an intricate network of posttranslational modifications and protein-protein interactions that provide integrated cellular response to changing physiological conditions and cues. AKT was identified in early genetic and biochemical studies as a main regulator of FoxO function in diverse organisms. Though other FoxO regulatory pathways and mechanisms have been delineated since, AKT remains a key regulator of the pathway. The present review summarizes the current knowledge of FoxO regulation by AKT and 14-3-3 proteins, focusing on its mechanistic and structural aspects and discusses its crosstalk with the other FoxO regulatory mechanisms. This article is part of a Special Issue entitled: PI3K-AKT-FoxO axis in cancer and aging. 2011 Elsevier B.V. All rights reserved.
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              ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.

              Jer-Yen Yang, Cong Zong, Weiya Xia … (2008)
              The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that Erk downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the non-phosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Fitoterapia
                Title: Fitoterapia
                Publisher: Elsevier BV
                ISSN (Electronic): 1873-6971
                ISSN (Print): 0367-326X
                Publication date (Electronic): Mar 2024
                Volume: 173
                Affiliations
                [1 ] Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, India.
                [2 ] Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, India. Electronic address: ekas2009@buc.edu.in.
                Article
                Publisher Item ID: S0367-326X(23)00382-9
                DOI: 10.1016/j.fitote.2023.105807
                PubMed ID: 38168566
                SO-VID: 5a94b208-d335-4f91-9b04-34b14822e6d5
                History

                Keywords: Apoptosis,FOXO3a,Natural bioactive compounds,Cancer,PI3K/Akt
                Data availability:
                Keywords: Apoptosis, FOXO3a, Natural bioactive compounds, Cancer, PI3K/Akt

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