AKT as locus of cancer positive feedback loops and extreme robustness

Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston Massachusetts 02115. .
Journal of Cellular Physiology (Impact Factor: 3.84). 03/2013; 228(3). DOI: 10.1002/jcp.24167
Source: PubMed

ABSTRACT A positive feedback loops induce extreme robustness in metastatic cancer, relapsed leukemia, myeloma or lymphoma. The loops are generated by the signaling interactome networks of auocrine and paracrine elements from cancer hypoxic microenvironment. The elements of the networks are signaling proteins synthesized in hypoxic microenvironment such as the VEGF, HIF-1α, HGF, and molecule H(2) O(2) . The signals from upstream or rebound downstream pathways are amplified by the short or wide positive feedback loops, hyperstimulating AKT inducing cancer extreme robustness. Targeting the phosphorylated AKT locus by an oxidant/antioxidant modulation induces collapse of positive feedback loops and establishment of negative feedback loops leading to stability of the system and disappearance of cancer extreme robustness. This is a new principle for the conversion of cancer positive loops into negative feedback loops by the locus chemotherapy. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.

4 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Complexity and robustness of cancer hypoxic microenvironment are supported by the robust signaling networks of autocrine and paracrine elements creating powerful interactome for multidrug resistance. These elements generate a positive feedback loops responsible for the extreme robustness and multidrug resistance in solid cancer, leukemia, myeloma and lymphoma. Phosphorylated AKT is a cancer multidrug resistance locus. Targeting that locus by oxidant/antioxidant balance modulation, positive feedback loops are converted into negative feedback loops, leading to disappearance of multidrug resistance. This is a new principle for targeting cancer multidrug resistance by the locus chemotherapy inducing a phenomenon of loops conversion. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 04/2013; 228(4). DOI:10.1002/jcp.24176 · 3.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A cancer angiogenesias is a complex system. Its robustness is supported by the signaling elements from cancer hypoxic microenvironment. The signaling angiogenic networks have nodal organization of its elements. The AKT is crucial macromolecule in the nodal angiogenic system of solid cancers, leukemia, lymphoma, plasmocytoma and myeloma. Targeting AKT locus by the locus chemotherapy, angiogenesis and all cancer system will fail. The AKT dephosphorylation phenomenon is induced by the redox balance change, causing conversion of the positive loops into normal feedback loops and leading to abolishment of cancer angiogenesis and cancer progression
    11/2013; 2(4):e106. DOI:10.4172/2329-6577.1000e106
  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein kinases regulate many processes, including cell growth, metabolism, molecular interactions, and cell proliferation. Protein kinase B (PKB)/AKT (v-AKT mouse thymoma viral oncogene homolog) is an upstream component of mammalian target of rapamycin (mTOR) signaling and mediates pathophysiological processes in several signaling pathways. This study aimed to construct and overexpress a eukaryotic goat AKT expression vector in goat fetal fibroblasts and examine the effects of AKT on the phosphorylation of p70S6K and 4E-BP1. AKT was subcloned into the expression vector pIRES2-DsRed2 to generate pIRES2-DsRed2-AKT, which was transfected into goat fetal fibroblasts with LipofectamineTM 2000. AKT was measured by reverse transcription-polymerase chain reaction in the transgenic cells, and the expression of AKT and phosphorylation of p70S6K (Thr389) and 4E-BP1 (Thr37/46) were analyzed by Western blot. Cell clones that stably emitted red fluorescence were obtained after transfection for 48 h, and the exogenous gene was verified. Exogenous AKT was transcribed, and AKT was overexpressed, inducing the phosphorylation of p70S6K (Thr389) and 4E-BP1 (Thr37/46) in goat fetal fibroblasts. Thus, the overexpression of AKT activates mTOR signaling in goat cells.
    Genetics and molecular research: GMR 11/2014; 13(4):9931-9938. DOI:10.4238/2014.November.27.22 · 0.78 Impact Factor
Show more