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Cell signaling pathways; oncogenes and tumor suppressor genes

Study the regulation of Akt signaling pathway in cancer.

The PI3K/Akt signaling pathway is upregulated in variety of human cancers. Akt (also known as PKB) is an important molecule in cellular survival pathways. Activated/phosphorylated Akt (pAkt) is able to induce protein synthesis pathways and is therefore a key protein involved in general tissue growth and prevention of apoptosis. There are several protein phosphatases that may regulate or dephosphorylate Akt. Nuclear localization of pAkt is crucial for its activity and function. Previously, I have focused on the mechanism behind rapid nuclear pAkt depletion. Previously, it was demonstrated in epidemiological studies that the cholesterol-lowering statins are associated with reduce risk multiple type of cancers. We found that statins mediated a rapid nuclear pAkt depletion. We focused therefore on the mechanism behind this rapid nuclear pAkt depletion. Our data indicates that the anticancer effect of statins might be mediated by inhibition of the Akt pathway. We have also characterized crosstalk between PHLPPs and PTEN, two proteins that down-regulate Akt activity. This crosstalk was seen in prostate cancer cells and TGFβ-1-activated prostate stem cells and had an impact on cellular invasiveness.

My results also suggest the involvement of several phosphatases, a PI3K subunit, certain membrane proteins and the P2X7 purinergic receptor. While the results are not applicable as direct interventions, they support previous observations in epidemiological studies and focus on critical cellular mechanisms capable of providing novel ideas for new human studies. These results also gave suggestions for new therapy areas and identify depletion of phosphorylated nuclear Akt as an interesting target for cancer prevention research.

Selected Publications:

  1. Ghalali A*, Ye Z, Högberg J, and Stenius Ulla. PTEN and PHLPP Crosstalk in Cancer Cells and in TGFβ-Activated Stem Cells. Biomedicine & Pharmacotherapy 2020 Mars, BIOPHA_BIOPHA-D-20-00762. *indicates position as corresponding author.
  2. Ghalali A, Martin-Renedo J, Högberg J, Stenius U. Atorvastatin Decreases HBx-Induced Phospho-Akt in Hepatocytes via P2X Receptors. Mol Cancer Res. 2017 Jun;15(6):714-722.
  3. Ghalali A, Wiklund F, Zheng H, Stenius U, Högberg J. Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells. Carcinogenesis. 2014 Jul;35(7):1547-55. Doi: 10.1093/carcin/bgu019.
  4. Ye ZW, Ghalali A, Högberg J, Stenius U. Silencing p110β prevents rapid depletion of nuclear pAkt. Biochem Biophys Res Commun. 2011 Dec 2;415(4):613-8. doi: 10.1016/j.bbrc.2011.10.120.
  5. Mistafa O#, Ghalali A#, Kadekar S, Högberg J, Stenius U. Purinergic receptor-mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine-rich repeat phosphatase, calcineurin, protein phosphatase 2A, and PTEN phosphatases. J Biol Chem. 2010 Sep 3;285(36):27900-10. doi: 10.1074/jbc.M110.117093. (*indicates position as corresponding author, #denotes equal contribution).