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Interplay Among PI3K/AKT, PTEN/FOXO and AR Signaling in Prostate Cancer

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Prostate Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1210))

Abstract

The PI3K signaling pathway is activated in a majority of cancer types. It promotes tumorigenesis by regulating nutrient metabolism, cell proliferation, survival, migration, and angiogenesis. The underlying mechanisms of PI3K/AKT activation are mainly due to deletions or mutations in its key negative regulator gene—PTEN. However, mutations in other pathway genes, such as the tumor suppressor gene SPOP, may contribute indirectly to the activation of this pathway. Interestingly, a mutually exclusive relationship exists between genomic alterations in PTEN and mutations in SPOP in prostate cancer patients, suggesting that altered functions of these two tumor suppressors might share similar or at least partially overlapping mechanisms in tumorigenesis. Activated AKT can phosphorylate directly a number of downstream effectors and thereby inhibit or activate their functions. An important target of PI3K/AKT signaling is FOXO1 protein that can be phosphorylated directly by AKT leading to translocation of FOXO1 from the cytoplasm to the nucleus. This not only impairs FOXO1 activities on transactivation of downstream target genes, but also abolishes its transcriptional activity-independent inhibitory effect on other targets such as AR, ERG and RUNX2. Interestingly, heterozygous deletion of Pten, or mutation of Spop alone has minimal effects on tumorigenesis in the mouse prostate, suggesting that PI3K/AKT pathway interacts with other pathways to drive prostate cancer progression. Indeed, the cross talk between PI3K/AKT and other pathways, such as AR, WNT, and ERK signaling pathways is known to play essential roles in disease progression and drug resistance in prostate cancer. Therefore, co-targeting the PI3K/AKT signaling pathway and its cooperating pathways may be critical for improving the anti-cancer efficacy of PI3K/AKT inhibitors in the clinic.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Yuqian Yan & Haojie Huang

  2. Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Haojie Huang

  3. Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Haojie Huang

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  1. Yuqian Yan
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  2. Haojie Huang
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Correspondence to Haojie Huang .

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Editors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Department of Urology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Scott M. Dehm

  2. Departments of Urology, and Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA

    Donald J. Tindall

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Yan, Y., Huang, H. (2019). Interplay Among PI3K/AKT, PTEN/FOXO and AR Signaling in Prostate Cancer. In: Dehm, S., Tindall, D. (eds) Prostate Cancer. Advances in Experimental Medicine and Biology, vol 1210. Springer, Cham. https://doi.org/10.1007/978-3-030-32656-2_14

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