AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci

Department of Pathology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
Frontiers in Bioscience (Impact Factor: 3.52). 02/2005; 10:975-87.
Source: PubMed


During the past decade, Akt (also known as protein kinase B, PKB) has been extensively studied. It regulates a variety of cellular processes by mediating extracellular (mitogenic growth factor, insulin and stress) and intracellular (altered tyrosine receptor kinases, Ras and Src) signals. Activation of Akt by these signals is via its pleckstrin homology (PH) domain binding to products of phosphatidylinositol 3-kinase (PI3K). This process is negatively regulated by a dual phosphatase PTEN tumor suppressor. Today, more than 30 Akt substrates have been identified. These phosphorylation events mediate the effects of Akt on cell survival, growth, differentiation, angiogenesis, migration and metabolism. Further, PI3K/PTEN/Akt pathway is frequently altered in many human malignancies and overexpression of Akt induces malignant transformation and chemoresistance. Thus, the Akt pathway is a major target for anti-cancer drug development. This review focuses on Akt signaling mechanism in oncogenesis and chemoresistance, and ongoing translational efforts to therapeutically target Akt.

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Available from: Sungman Park, Oct 01, 2015
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    • "After C35 was identified and characterised as a novel protein binding partner of ΔNp73 that has a significant role in cancer cell progression and chemo-resistance, we studied the molecular mechanisms underlying the enhancement of ovarian cancer progression by the C35–ΔNp73 interaction. It is well known that the AKT signalling pathway is associated with chemo-resistance in human cancers (Brognard et al, 2001; Li et al, 2001; Fraser et al, 2003; Dan et al, 2004; Pommier et al, 2004; Kim et al, 2005; Abedini et al, 2010). TAp73 and ΔNp73 have also been suggested to have important roles in the sensitivity of cancer cells to drug-induced apoptosis (Irwin et al, 2003; Vayssade et al, 2005; Al-Bahlani et al, 2011). "
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    ABSTRACT: Background: The purpose of this study was to characterise the oncogenic roles of C35, a novel protein binding partner of ΔNp73, in ovarian cancer and to investigate the functional significance of C35–ΔNp73 interaction in the regulation of chemo-resistance. Methods: C35 expression was evaluated by quantitative real-time PCR in human ovarian cancer tissues and cell lines. The aggressiveness of ovarian cancer cells overexpressing C35 was examined by cell proliferation, migration, soft agar and nude mouse xenograft. The significance of C35–ΔNp73 interaction in chemo-resistance was evaluated by apoptosis assays and cell viability after cisplatin treatment. Results: The expression of C35 was significantly enhanced in human ovarian cancer tissues. Overexpression of C35 augmented proliferation, migration and tumourigenicity in ovarian cancer cell lines. C35 knockdown inhibited cell motility and cell growth. The co-expression of C35 and ΔNp73 by transient or stable transfection in ovarian cancer cells induced greater resistance to cisplatin treatment than did transfection with C35 or ΔNp73 alone. The cisplatin resistance was demonstrated to be caused by increased AKT and NFκB activity induced by C35–ΔNp73. Conclusion: Our results suggest that ΔNp73 might cooperate with C35 to promote tumour progression and contribute to cisplatin resistance in ovarian cancer cells. Future studies of the functional roles of ΔNp73 and C35 will provide insight that will aid in the establishment of new strategies and more effective therapies.
    British Journal of Cancer 07/2013; 109(4). DOI:10.1038/bjc.2013.397 · 4.84 Impact Factor
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    • "Previous studies (4,16) have shown that CDDP resistance is associated with AKT overexpression. The activation of AKT promotes the development of resistance to chemotherapy treatment (17–19). In the present study, JAK2, activated by CDDP-induced ROS, was associated with STAT3 phosphorylation and the transactivation of a STAT-targeted AKT gene promoter. "
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    ABSTRACT: The use of chemotherapy drugs for the treatment of cancer is an effective therapeutic measure. However, chemoresistance affects the effectiveness of the treatment. AKT overexpression has been observed in chemoresistance. AKT expression in colon cells induced cisplatin resistance. The present study demonstrated the role of reactive oxygen species (ROS) in the induction of AKT regulation by cisplatin through the activation of JAK2/STAT3 at the transcriptional level in colon cancer cells. HCT-116 cells treated with cisplatin exhibited increased JAK2 and STAT3 activities. Reducing the expression of JAK2 in colon cancer cells using small interfering RNA (siRNA) decreased AKT expression. The present study demonstrated that AKT activation is closely associated with chemoresistance in human tumors. The inhibition of ROS decreased the levels of AKT in colon cancer cell lines. The JAK2/STAT3 pathway was also shown to mediate AKT expression and represents a potential target for overcoming cisplatin resistance in human tumors.
    Oncology letters 03/2013; 5(3):756-760. DOI:10.3892/ol.2013.1132 · 1.55 Impact Factor
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    • "Akt: Akt, also known as protein kinase B, PKB, is a SH2-like (SRC homology 2-like) domain containing serine-threonine protein kinase and is activated by binding to the products of PI3K. Of the three isoforms of Akt, Akt 2 is frequently amplified in human malignancies, though alterations at protein and kinase levels are observed with all isoforms [47]. Amplifications in multiple Akt isoforms have been reported in pancreatic, ovarian, and head and neck cancers [48]. "
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    ABSTRACT: Platinum based drugs are widely used to treat various types of cancers by inducing DNA damage mediated cytotoxicity. However, acquirement of chemoresistance towards platinum based drugs is a common phenomenon and a major hurdle in combating the relapse of the disease. Oncogenesis and chemoresistance are multifactorial maladies which often involve deregulation of one of the prime cell survival pathways, the PI3K/Akt/mTOR signalling cascade. The genetic alterations related to this pathway are often responsible for initiation and/or maintenance of carcinogenesis. Molecular components of this pathway are long being recognized as major targets for therapeutic intervention and are now also have emerged as potential tools for diagnosis of cancer. To develop novel therapeutics against the key molecules of PI3K pathway, stringent validation is required using both in-vitro and in-vivo models. Repetitive and non-invasive molecular imaging techniques, a relatively recent field in biomedical imaging hold great promises for monitoring such diagnosis and therapy. In this review, we first introduced the PI3K/Akt/mTOR pathway and its role in acquirement of chemoresistance in various cancers. Further we described how non-invasive molecular imaging approaches are sought to use this PI3K signalling axis for the therapeutics and diagnosis. A theranostic approach using various imaging modalities should be the future of PI3K signalling based drug development venture.
    American Journal of Nuclear Medicine and Molecular Imaging 11/2012; 2(4):418-31. · 3.25 Impact Factor
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