alexa Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells.
Oncology

Oncology

Journal of Oncology Translational Research

Author(s): Soares HP, Ni Y, Kisfalvi K, SinnettSmith J, Rozengurt E

Abstract Share this page

Abstract The mTOR pathway is aberrantly stimulated in many cancer cells, including pancreatic ductal adenocarcinoma (PDAC), and thus it is a potential target for therapy. However, the mTORC1/S6K axis also mediates negative feedback loops that attenuate signaling via insulin/IGF receptor and other tyrosine kinase receptors. Suppression of these feed-back loops unleashes over-activation of upstream pathways that potentially counterbalance the antiproliferative effects of mTOR inhibitors. Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic cancer cells with either rapamycin or active-site mTOR inhibitors suppressed S6K and S6 phosphorylation induced by insulin and the GPCR agonist neurotensin. Rapamycin caused a striking increase in Akt phosphorylation at Ser(473) while the active-site inhibitors of mTOR (KU63794 and PP242) completely abrogated Akt phosphorylation at this site. Conversely, active-site inhibitors of mTOR cause a marked increase in ERK activation whereas rapamycin did not have any stimulatory effect on ERK activation. The results imply that first and second generation of mTOR inhibitors promote over-activation of different pro-oncogenic pathways in PDAC cells, suggesting that suppression of feed-back loops should be a major consideration in the use of these inhibitors for PDAC therapy. In contrast, metformin abolished mTORC1 activation without over-stimulating Akt phosphorylation on Ser(473) and prevented mitogen-stimulated ERK activation in PDAC cells. Metformin induced a more pronounced inhibition of proliferation than either KU63794 or rapamycin while, the active-site mTOR inhibitor was more effective than rapamycin. Thus, the effects of metformin on Akt and ERK activation are strikingly different from allosteric or active-site mTOR inhibitors in PDAC cells, though all these agents potently inhibited the mTORC1/S6K axis.
This article was published in PLoS One and referenced in Journal of Oncology Translational Research

Relevant Expert PPTs

Relevant Speaker PPTs

  • Chunmei Shi
    Children's eating behaviors and maternal feeding practices are associated with child body mass index in 1- to 7-year-old children
    PPT Version | PDF Version
  • Ping Gu
    Myeloid-specific deletion of SIRT1 impairs obesity and ageing-associated endothelial dysfunction
    PPT Version | PDF Version
  • Hedef Dhafir El-Yassin
    The Immune Response of Prolactin and the Induction of Tumor Necrosis Factor (TNF) in Iraqi Patients Infected with Hepatitis C Virus
    PPT Version | PDF Version
  • Moshe Giladi
    Tumor Treating Fields (TTFields) induced cancer cell death may be immunogenic resulting in enhanced antitumor efficacy when combined with immune-modulating therapy
    PPT Version | PDF Version
  • Sumru Savas
    No relationship between lipoprotein-associated phospholipase A2, proinflammatory cytokines, and neopterin   in Alzheimer's disease
    PPT Version | PDF Version
  • Eltayeb Tayrab
    Human mercury exposure associated with artisanal gold miners in Sudan
    PPT Version | PDF Version
  • Mustafa M Hariri
    Importance of methods’ selection in the geosciences studies and exploration
    PPT Version | PDF Version
  • Peter S. Nyasulu
    Prevalence and risk factors associated with acquisition of Sexually Transmitted Infections among people living with Human Immunodeficiency Virus in Diepsloot settlement, Johannesburg, South Africa
    PPT Version | PDF Version
  • Sruthi Ramagiri
    Beneficial neuroprotective effect of GSK-3β inhibitors against brain stroke and associated cognitive impairments in diabetic rats
    PPT Version | PDF Version
  • Stefan B Eichmüller
    Identification of CD4+ T cell epitopes specific for the breast cancer associated antigen NY-BR-1
    PDF Version
  • M Shahnawaz Khan
    Graphene Oxide @ Gold Nanorods Conjugate for Controlled Release of Doxorubicin in tumor
    PPT Version | PDF Version
  • Omar E Franco
    Heterogeneous Tumor Stroma and Prostate Carcinogenesis
    PPT Version | PDF Version
  • Yen-Chein Lai
    Molecular pathogenesis in granulosa cell tumor is not only due to somatic FOXL2 mutation
    PPT Version | PDF Version
  • Babak Behnam
    SLUG and SOX9 Cooperatively Regulate Tumor Initiating Niche Factors in Breast Cancer
    PPT Version | PDF Version
  • Yosef Yarden
    Classically, the 3’untranslated region (3’UTR) is that region in eukaryotic protein-coding genes from the translation termination codon to the polyA signal. It is transcribed as an integral part of the mRNA encoded by the gene. However, there exists another kind of RNA, which consists of the 3’UTR alone, without all other elements in mRNA such as 5’UTR and coding region. The importance of independent 3’UTR RNA (referred as I3’UTR) was prompted by results of artificially introducing such RNA species into malignant mammalian cells. Since 1991, we found that the middle part of the 3’UTR of the human nuclear factor for interleukin-6 (NF-IL6) or C/EBP gene exerted tumor suppression effect in vivo. Our subsequent studies showed that transfection of C/EBP 3’UTR led to down-regulation of several genes favorable for malignancy and to up-regulation of some genes favorable for phenotypic reversion. Also, it was shown that the sequences near the termini of the C/EBP 3’UTR were important for its tumor suppression activity. Then, the C/EBP 3’UTR was found to directly inhibit the phosphorylation activity of protein kinase CPKC in SMMC-7721, a hepatocarcinoma cell line. Recently, an AU-rich region in the C/EBP 3’UTR was found also to be responsible for its tumor suppression. Recently we have also found evidence that the independent C/EBP 3’UTR RNA is actually exists in human tissues, such as fetal liver and heart, pregnant uterus, senescent fibroblasts etc. Through 1990’s to 2000’s, world scientists found several 3’UTR RNAs that functioned as artificial independent RNAs in cancer cells and resulted in tumor suppression. Interestingly, majority of genes for these RNAs have promoter-like structures in their 3’UTR regions, although the existence of their transcribed products as independent 3’UTR RNAs is still to be confirmed. Our studies indicate that the independent 3’UTR RNA is a novel non-coding RNA species whose function should be the regulation not of the expression of their original mRNA, but of some essential life activities of the cell as a whole.
    PPT Version | PDF Version

Recommended Conferences

  • International Conference on Cancer & Tumor Immunology
    July 03-05, 2017 Bangkok,Thailand
  • 2nd International Conference on Tumor & Cancer Immunology and Immunotherapy
    July 17-19, 2017 Chicago, USA
  • Global Experts meeting on Oncology Case Reports
    Aug 29-31, 2017 London, UK
  • 25th World Congress on Cancer Science and Therapy
    October 18-20, 2017 Baltimore, Maryland, USA
  • 25th World Cancer Conference
    Oct 19-21, 2017 Rome, Italy
Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords