Elsevier

Seminars in Cancer Biology

Volume 35, December 2015, Pages 180-190
Seminars in Cancer Biology

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

https://doi.org/10.1016/j.semcancer.2015.07.003Get rights and content

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a key cascade downstream of several protein kinases, especially membrane-bound receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) family members. Hyperactivation of the PI3K/Akt pathway is correlated with tumor development, progression, poor prognosis, and resistance to cancer therapies, such as radiotherapy, in human solid tumors. Akt/PKB (Protein Kinase B) members are the major kinases that act downstream of PI3K, and these are involved in a variety of cellular functions, including growth, proliferation, glucose metabolism, invasion, metastasis, angiogenesis, and survival. Accumulating evidence indicates that activated Akt is one of the major predictive markers for solid tumor responsiveness to chemo/radiotherapy. DNA double-strand breaks (DNA-DSB), are the prime cause of cell death induced by ionizing radiation. Preclinical in vitro and in vivo studies have shown that constitutive activation of Akt and stress-induced activation of the PI3K/Akt pathway accelerate the repair of DNA-DSB and, consequently, lead to therapy resistance. Analyzing dysregulations of Akt, such as point mutations, gene amplification or overexpression, which results in the constitutive activation of Akt, might be of special importance in the context of radiotherapy outcomes. Such studies, as well as studies of the mechanism(s) by which activated Akt1 regulates repair of DNA-DSB, might help to identify combinations using the appropriate molecular targeting strategies with conventional radiotherapy to overcome radioresistance in solid tumors. In this review, we discuss the dysregulation of the components of upstream regulators of Akt as well as specific modifications of Akt isoforms that enhance Akt activity. Likewise, the mechanisms by which Akt interferes with repair of DNA after exposure to ionizing radiation, will be reviewed. Finally, the current status of Akt targeting in combination with radiotherapy will be discussed.

Introduction

Radiotherapy, with chemotherapy and surgery, is a major cancer treatment modality used to treat approximately 50% of all cancer patients, with varying success. The dose of irradiation that can be given to a tumor is determined by the radiosensitivity of the surrounding normal tissues [1] as well as the intrinsic sensitivity/resistance of the tumor. Resistance to radiotherapy can be due either to intrinsic radioresistance or an acquired resistance during fractionated radiotherapy. One of the molecular events by which tumors become radioresistant is radiation-induced activation of signal transduction pathways, such as those regulated by membrane-bound receptor tyrosine kinases (RTKs) in a ligand-independent manner. In this context, the role of erbB family of receptors, especially epidermal growth factor receptor (EGFR), has been extensively investigated. In tumor cells, activation of EGFR stimulates signal transduction pathways that ultimately promote tumor cell proliferation, survival, migration, invasion, and angiogenesis [2], [3]. This leads to both chemo- and radiotherapy resistance and, consequently, to a poor prognosis [4], [5], [6]. The pro-survival effect of EGFR is mediated either by nuclear accumulation of EGFR [7], [8] or by activation of various downstream signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, the signal transducer and activator of transcription (STAT) pathway and the Ras-mitogen-activated protein kinase (MAPK) pathway [9], [10], [11]. The PI3K/Akt pathway is one of the major survival pathways in cancer cells, and it is frequently upregulated in human tumors [12], [13]. PI3Ks are divided into three classes according to their structural characteristics and substrate specificity [14]. Class I PI3Ks are further divided into class IA enzymes—which are activated by membrane-bound RTKs, G-protein-coupled receptors (GPCRs), and certain oncogenes such as the small G protein Ras—and class IB enzymes, which are regulated exclusively by GPCRs [12], [14]. Class IA PI3Ks are heterodimers that consist of a p110 catalytic subunit and a p85 regulatory subunit that, when activated, convert phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3) at the membrane, providing docking sites for signaling proteins with pleckstrin-homology (PH) domains, including phosphoinositide-dependent kinase 1 (PDK1) and the Ser–Thr kinase Akt [12]. Although Akt1, when phosphorylated at the T308 residue, is active, full activation requires an additional phosphorylation at S473 by a different kinase, PDK2 [15]. So far, the kinase(s) functioning as PDK2 is/are not well described. Existing reports support both, autophosphorylation as well as phosphorylation by other kinases including ATM [16] and DNA-PKcs [17], the integrin-linked kinase 1 [18], and the mammalian target of rapamycin (mTOR)-rictor [19]. The PI3K/Akt pathway is hyperactivated in a wide range of tumor types, especially in tumors presenting a mutation in one of the components of the EGFR downstream pathways, such as phosphatase and tensin homolog (PTEN), a negative regulator of PI3K, PIK3CA and Ras [20], [21]. Mutational activation of Ras and PI3K is accompanied by resistance to radio-/chemotherapy [22], [23], [24], [25]. Thus, the activity status of the PI3K pathway in the cytoplasm as well as in the nuclear compartment due to overexpression of RTKs or mutations in signaling components, might be a predictive marker for the responsiveness of tumor cells to radiotherapy. Akt, which is also known as protein kinase B (PKB), is a canonical downstream signaling effector of PI3K and an oncogene with critical roles involved in a number of important cellular processes, including cell growth, proliferation, survival, invasion, metastasis, and angiogenesis. [26]. In addition to these well-described functions, accumulating evidence indicates that Akt is directly involved in the control of DNA repair and radioresistance. In this review, the expression and activity of Akt isoforms in cancers with different origins will be summarized. We also review the role of Akt family members, especially Akt1, in radioresistance in solid tumors and summarize the role of Akt in the context of DNA double-strand break repair.

Section snippets

Role of Akt/PKB in human cancers

Akt/PKB is a serine/threonine kinase, which exists in three isoforms known as Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ). Although Akt isoforms are encoded by different genes on chromosomes 14q32, 19q13, and 1q44, respectively, their amino acid sequences share approximately 80% similarity [27]. Akt isoforms each contain three similar domains – pleckstrin homology, kinase and regulatory domains – and the isoforms are localized in distinct sub-cellular compartments [15], [28]. Akt isoforms have

Importance of Akt in radiotherapy resistance

Membrane-bound RTKs consist of 58 members that are distributed in 20 subfamilies [90]. These families of receptors are important regulators of intracellular signal-transduction pathways. Mutations and other genetic alterations result in deregulated kinase activity and the activation of downstream signaling pathways. PI3K is a crucial effector in RTK signaling, which leads to the activation of many substrates. Among those substrates activated by PI3K, Akt is one of the most important [12].

Control of DNA damage by Akt as an important mechanism for radioresistance

Previous reports showed a direct EGFR-Akt correlation, indicating that EGFR was a major regulator of Akt-dependent DNA-DSB repair [97], [163], [164], [165] after irradiation. Moreover, the impact of Akt activity on DNA-DSB repair and radioresistance in tumor cells from different origins has also been demonstrated [23], [102], [128], [166], [167]. DNA-DSB are the most lethal type of DNA lesions that lead to cell death following exposure to ionizing radiation [168]. The two pathways involved in

Akt inhibitors in cancer therapy

Extensive crosstalk at different levels between the PI3K/Akt pathway and the MAPK/ERK pathway is an obstacle to single-targeting PI3K in tumors, suggesting that combined inhibition of both pathways may achieve synergistic antitumor activity [197]. In addition to the previously described crosstalk between these two pathways, we identified a novel crosstalk mechanism by which 24 h inhibition of PI3K by PI-103 [198] or LY294002 (Toulany and Rodemann, unpublished data) resulted in the MAPK-dependent

Conclusion

Understanding the function of cellular signaling pathways involved in tumor growth, proliferation and survival is important for designing molecular targeting approaches in oncology. Activation of the PI3K/Akt signaling pathway is crucial for post-irradiation cell survival. Most of the small-molecule inhibitors used to target signal components within this pathway are cytostatic rather than cytotoxic. Likewise, hyperactivation of the downstream components of this pathway, such as mutations in

Conflicts of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

Supported by grants from the Deutsche Forschungsgemeinschaft, Germany (Ro527/7-1 and SFB-773-TP B02) awarded to HPR, GRK 1302/2 (T11) awarded to MT/HPR.

References (213)

  • A. Bellacosa et al.

    Activation of AKT kinases in cancer: Implications for therapeutic targeting

    Adv. Cancer Res.

    (2005)
  • K.J. Hatanpaa et al.

    Epidermal growth factor receptor in glioma: Signal transduction, neuropathology, imaging, and radioresistance

    Neoplasia

    (2010)
  • M. Minjgee et al.

    K-RAS(V12) induces autocrine production of EGFR ligands and mediates radioresistance through EGFR-dependent Akt signaling and activation of DNA-PKcs

    Int. J. Radiat. Oncol. Biol. Phys.

    (2011)
  • M. Toulany et al.

    Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway

    Radiother. Oncol.

    (2005)
  • K. Kurose et al.

    Frequent loss of PTEN expression is linked to elevated phosphorylated Akt levels, but not associated with p27 and cyclin D1 expression, in primary epithelial ovarian carcinomas

    Am. J. Pathol.

    (2001)
  • Y. Dobashi et al.

    Molecular alterations in AKT and its protein activation in human lung carcinomas

    Hum. Pathol.

    (2012)
  • Y. Cohen et al.

    AKT1 pleckstrin homology domain E17K activating mutation in endometrial carcinoma

    Gynecol. Oncol.

    (2010)
  • M.M. Hill et al.

    Inhibition of protein kinase B/Akt. implications for cancer therapy

    Pharmacol. Ther.

    (2002)
  • H. Makinoshima et al.

    Signaling through the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) axis is responsible for aerobic glycolysis mediated by glucose transporter in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma

    J. Biol. Chem.

    (2015)
  • K. Nakatani et al.

    Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines

    J. Biol. Chem.

    (1999)
  • M.M. Nijkamp et al.

    Spatial relationship of phosphorylated epidermal growth factor receptor and activated AKT in head and neck squamous cell carcinoma

    Radiother. Oncol.

    (2011)
  • U. Kasten-Pisula et al.

    Cellular and tumor radiosensitivity is correlated to epidermal growth factor receptor protein expression level in tumors without EGFR amplification

    Int. J. Radiat. Oncol. Biol. Phys.

    (2011)
  • K. Dittmann et al.

    Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access

    Radiother. Oncol.

    (2011)
  • S.M. Huber et al.

    EGFR-mediated stimulation of sodium/glucose cotransport promotes survival of irradiated human A549 lung adenocarcinoma cells

    Radiother. Oncol.

    (2012)
  • M. Toulany et al.

    Radiosensitization of Ras-mutated human tumor cells in vitro by the specific EGF receptor antagonist BIBX1382BS

    Radiother. Oncol.

    (2005)
  • A.C. Begg et al.

    Strategies to improve radiotherapy with targeted drugs

    Nat. Rev. Cancer

    (2011)
  • M.K. Nyati et al.

    Integration of EGFR inhibitors with radiochemotherapy

    Nat. Rev. Cancer

    (2006)
  • S.M. Huang et al.

    Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: Inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis

    Clin. Cancer Res.

    (2000)
  • K.K. Ang et al.

    Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma

    Cancer Res.

    (2002)
  • J.L. Nakamura

    The epidermal growth factor receptor in malignant gliomas: Pathogenesis and therapeutic implications

    Expert Opin. Ther. Targets

    (2007)
  • D.L. Wheeler et al.

    Understanding resistance to EGFR inhibitors-impact on future treatment strategies

    Nat. Rev. Clin. Oncol.

    (2010)
  • H.P. Rodemann et al.

    Radiation-induced EGFR-signaling and control of DNA-damage repair

    Int. J. Radiat. Biol.

    (2007)
  • M. Toulany et al.

    Membrane receptor signaling and control of DNA repair after exposure to ionizing radiation

    Nuklearmedizin

    (2010)
  • P. Liu et al.

    Targeting the phosphoinositide 3-kinase pathway in cancer

    Nat. Rev. Drug Discov.

    (2009)
  • Z. Liu et al.

    Human tumor mutants in the p110alpha subunit of PI3K

    Cell Cycle

    (2006)
  • J.A. Engelman et al.

    The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

    Nat. Rev. Genet.

    (2006)
  • S.A. Santi et al.

    The Akt isoforms are present at distinct subcellular locations

    Am. J. Physiol. Cell Physiol.

    (2010)
  • S. Persad et al.

    Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • D.D. Sarbassov et al.

    Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

    Science

    (2005)
  • W.G. McKenna et al.

    The RAS signal transduction pathway and its role in radiation sensitivity

    Oncogene

    (2003)
  • K.R. Sekhar et al.

    The novel chemical entity YTR107 inhibits recruitment of nucleophosmin to sites of DNA damage, suppressing repair of DNA double-strand breaks and enhancing radiosensitization

    Clin. Cancer Res.

    (2011)
  • S. Misale et al.

    Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer

    Nature

    (2012)
  • I. Garrido-Laguna et al.

    KRASness and PIK3CAness in patients with advanced colorectal cancer: Outcome after treatment with early-phase trials with targeted pathway inhibitors

    PLoS One

    (2012)
  • M. Cheung et al.

    Diverse mechanisms of AKT pathway activation in human malignancy

    Curr. Cancer Drug Targets

    (2013)
  • S.S. Murthy et al.

    Mapping of AKT3, encoding a member of the Akt/protein kinase B family, to human and rodent chromosomes by fluorescence in situ hybridization

    Cytogenet. Cell Genet.

    (2000)
  • S.A. Santi et al.

    The Akt isoforms, their unique functions and potential as anticancer therapeutic targets

    Biomol. Concepts

    (2010)
  • B. Dummler et al.

    Physiological roles of PKB/Akt isoforms in development and disease

    Biochem. Soc. Trans.

    (2007)
  • J. LaRocca et al.

    Akt1 is essential for postnatal mammary gland development, function, and the expression of Btn1a1

    PLoS One

    (2011)
  • H. Cho et al.

    Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta)

    Science

    (2001)
  • R.M. Easton et al.

    Role for Akt3/protein kinase Bgamma in attainment of normal brain size

    Mol. Cell Biol.

    (2005)
  • Cited by (131)

    • Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives

      2023, Clinical and Translational Radiation Oncology
      Citation Excerpt :

      Oncogenic K-Ras hyperactivates the PI3K/AKT pathway. The PI3K/AKT pathway is the major survival pathway, which is hyperactivated in human tumors and is involved in DNA damage response (DDR) signaling, as reviewed elsewhere [20,21]. In terms of cell survival after RT, constitutive K-Ras activity due to RAS mutation or IR-induced Ras activation leads to accelerated repair of radiation-induced DSB and increased survival in solid tumors from different tissues [18,22–25].

    View all citing articles on Scopus
    View full text