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

Yuqian Yan, Haojie Huang

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations

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.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer
Pages319-331
Number of pages13
DOIs
StatePublished - Jan 1 2019

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1210
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Yan, Y., & Huang, H. (2019). Interplay Among PI3K/AKT, PTEN/FOXO and AR Signaling in Prostate Cancer. In Advances in Experimental Medicine and Biology (pp. 319-331). (Advances in Experimental Medicine and Biology; Vol. 1210). Springer. https://doi.org/10.1007/978-3-030-32656-2_14