Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation
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)
- et al.
Preclinical evaluation of molecular-targeted anticancer agents for radiotherapy
Radiother. Oncol.
(2006) - et al.
Nuclear EGFR protein expression predicts poor survival in early stage non-small cell lung cancer
Lung Cancer
(2013) - et al.
Responses of normal cells to ionizing radiation
Semin. Radiat. Oncol.
(2007) - et al.
Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM
J. Biol. Chem.
(2005) - et al.
Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase
J. Biol. Chem.
(2004) - et al.
Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells
Neoplasia
(2007) - et al.
Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation
J. Biol. Chem.
(2007) - et al.
Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice
J. Biol. Chem.
(2001) - et al.
Differential function of Akt1 and Akt2 in human adipocytes
Mol. Cell Endocrinol.
(2012) - et al.
AKT/PKB signaling: Navigating downstream
Cell
(2007)
Activation of AKT kinases in cancer: Implications for therapeutic targeting
Adv. Cancer Res.
Epidermal growth factor receptor in glioma: Signal transduction, neuropathology, imaging, and radioresistance
Neoplasia
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.
Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway
Radiother. Oncol.
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.
Molecular alterations in AKT and its protein activation in human lung carcinomas
Hum. Pathol.
AKT1 pleckstrin homology domain E17K activating mutation in endometrial carcinoma
Gynecol. Oncol.
Inhibition of protein kinase B/Akt. implications for cancer therapy
Pharmacol. Ther.
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.
Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines
J. Biol. Chem.
Spatial relationship of phosphorylated epidermal growth factor receptor and activated AKT in head and neck squamous cell carcinoma
Radiother. Oncol.
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.
Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access
Radiother. Oncol.
EGFR-mediated stimulation of sodium/glucose cotransport promotes survival of irradiated human A549 lung adenocarcinoma cells
Radiother. Oncol.
Radiosensitization of Ras-mutated human tumor cells in vitro by the specific EGF receptor antagonist BIBX1382BS
Radiother. Oncol.
Strategies to improve radiotherapy with targeted drugs
Nat. Rev. Cancer
Integration of EGFR inhibitors with radiochemotherapy
Nat. Rev. Cancer
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.
Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma
Cancer Res.
The epidermal growth factor receptor in malignant gliomas: Pathogenesis and therapeutic implications
Expert Opin. Ther. Targets
Understanding resistance to EGFR inhibitors-impact on future treatment strategies
Nat. Rev. Clin. Oncol.
Radiation-induced EGFR-signaling and control of DNA-damage repair
Int. J. Radiat. Biol.
Membrane receptor signaling and control of DNA repair after exposure to ionizing radiation
Nuklearmedizin
Targeting the phosphoinositide 3-kinase pathway in cancer
Nat. Rev. Drug Discov.
Human tumor mutants in the p110alpha subunit of PI3K
Cell Cycle
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
Nat. Rev. Genet.
The Akt isoforms are present at distinct subcellular locations
Am. J. Physiol. Cell Physiol.
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.
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Science
The RAS signal transduction pathway and its role in radiation sensitivity
Oncogene
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.
Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer
Nature
KRASness and PIK3CAness in patients with advanced colorectal cancer: Outcome after treatment with early-phase trials with targeted pathway inhibitors
PLoS One
Diverse mechanisms of AKT pathway activation in human malignancy
Curr. Cancer Drug Targets
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.
The Akt isoforms, their unique functions and potential as anticancer therapeutic targets
Biomol. Concepts
Physiological roles of PKB/Akt isoforms in development and disease
Biochem. Soc. Trans.
Akt1 is essential for postnatal mammary gland development, function, and the expression of Btn1a1
PLoS One
Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta)
Science
Role for Akt3/protein kinase Bgamma in attainment of normal brain size
Mol. Cell Biol.
Cited by (131)
Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives
2023, Clinical and Translational Radiation OncologyCitation 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].
A meta-learning approach to improving radiation response prediction in cancers
2022, Computers in Biology and MedicineTargeting HER3-dependent activation of nuclear AKT improves radiotherapy of non-small cell lung cancer
2022, Radiotherapy and OncologyUp-regulated FNDC1 accelerates stemness and chemoradiation resistance in colorectal cancer cells
2022, Biochemical and Biophysical Research Communications