Aram Ghalali1, Zhi-Wei Ye2, Johan Högberg3, Ulla Stenius3. 1. Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden. Electronic address: aram.ghalali@ki.se. 2. Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden; Department of Pharmacology, Medical University of South Carolina, United States. 3. Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Abstract
Akt kinase regulates several cellular processes, among them growth, proliferation and survival, and has been correlated to neoplastic disease. We report here crosstalk between several Akt regulatory phosphatases that controls the level of the activated form (phosphorylated) of Akt and affects tumor cell aggressiveness. In prostate cancer cell lines, we observed that transient transfection of PTEN decreased the endogenous level of PHLPPs and in contrast, the transient transfection of PHLPPs decreased the endogenous level of PTEN. Furthermore, silencing of PTEN by siRNA resulted in increased PHLPP levels. This phenomenon was not seen in non-transformed cells or in prostate stem cells. This crosstalk promoted cancer cell invasion and was controlled by epigenetically regulated processes where activation of miRs (miR-190 and miR214), the polycomb group of proteins and DNA methylation were involved. The purinergic P2X4 receptor, which has been shown to have a role in wound healing, was identified to be the mediator of this crosstalk. We also studied prostate stem cells and found this crosstalk in the TGFβ1-activated epithelial-mesenchymal transition (EMT). The crosstalk seemed to be a natural part of EMT. In summary, we identify a crosstalk between Akt phosphatases which is not present in non-transformed prostate cells but occurs in cancer cells and stem cells transformed by TGFβ-1. This crosstalk is important for cellular invasion. BACKGROUND: Phosphatases regulate the Akt oncogene. RESULTS: Crosstalk between Akt phosphatases in prostate cancer cells and in TGF-β1 activated stem cells but not in non-transformed cells. CONCLUSION: This back-up mechanism facilitates invasive migration of prostate stem and cancer cells. SIGNIFICANCE: Characterization of Akt regulation may lead to a better understanding of tumor development and to novel strategies for treatment.
Akt kinase regulates several cellular processes, among them growth, proliferation and survival, and has been correlated to neoplastic disease. We report here crosstalk between several Akt regulatory phosphatases that controls the level of the activated form (phosphorylated) of Akt and affects tumor cell aggressiveness. In prostate cancer cell lines, we observed that transient transfection of PTEN decreased the endogenous level of PHLPPs and in contrast, the transient transfection of PHLPPs decreased the endogenous level of PTEN. Furthermore, silencing of PTEN by siRNA resulted in increased PHLPP levels. This phenomenon was not seen in non-transformed cells or in prostate stem cells. This crosstalk promoted cancer cell invasion and was controlled by epigenetically regulated processes where activation of miRs (miR-190 and miR214), the polycomb group of proteins and DNA methylation were involved. The purinergic P2X4 receptor, which has been shown to have a role in wound healing, was identified to be the mediator of this crosstalk. We also studied prostate stem cells and found this crosstalk in the TGFβ1-activated epithelial-mesenchymal transition (EMT). The crosstalk seemed to be a natural part of EMT. In summary, we identify a crosstalk between Akt phosphatases which is not present in non-transformed prostate cells but occurs in cancer cells and stem cells transformed by TGFβ-1. This crosstalk is important for cellular invasion. BACKGROUND: Phosphatases regulate the Akt oncogene. RESULTS: Crosstalk between Akt phosphatases in prostate cancer cells and in TGF-β1 activated stem cells but not in non-transformed cells. CONCLUSION: This back-up mechanism facilitates invasive migration of prostate stem and cancer cells. SIGNIFICANCE: Characterization of Akt regulation may lead to a better understanding of tumor development and to novel strategies for treatment.
Authors: Janielle P Maynard; Jiayun Lu; Igor Vidal; Jessica Hicks; Luke Mummert; Tamirat Ali; Ryan Kempski; Ayanna M Carter; Rebecca Y Sosa; Lauren B Peiffer; Corinne E Joshu; Tamara L Lotan; Angelo M De Marzo; Karen S Sfanos Journal: J Pathol Date: 2021-11-25 Impact factor: 7.996