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Journal of Clinical Oncology, Vol 22, No 20 (October 15), 2004: pp. 4217-4226 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.103
Putting the Rap on AktFrom the Division of Hematology/Oncology, Department of Medicine, Department of Cancer Biology, University of Pennsylvania, Abramson Family Cancer Research Institute, Philadelphia, PA Address reprint requests to Craig B. Thompson, MD, University of Pennsylvania, Abramson Family Cancer Research Institute, 421 Curie Blvd, Room 450 BRB II/III, Philadelphia, PA 19104-6160; e-mail: craig{at}mail.med.upenn.edu
The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.
A cancer develops when the balance between generation and growth of new cells, and death and removal of excess cells is disrupted. These alterations can occur through excessive stimulation of growth and proliferation pathways, inhibition of cell death pathways, or, most often, a combination of these mechanisms. The serine-threonine kinase Akt was first discovered as a viral oncogene and has effects on both pathways. The role of Akt in stimulation of cell growth and proliferation has been reviewed elsewhere1-4; this review focuses on the role of the phosphoinositide 3-kinase (PI3-K)/Akt/phosphatase and tensin homolog deleted on chromosome 10 (PTEN) pathway in the inappropriate maintenance of cell survival, the implications of increased cell survival in a number of human malignancies, and some possible therapeutic opportunities using existing pharmacologic agents such as rapamycin.
Many growth factor receptors activate the lipid kinase PI3-K (Fig 1). Activated PI3-K generates membrane-bound phosphoinositides, which act as second messengers and serve to recruit proteins, such as Akt, which contain a pleckstrin homology (PH) domain. After recruitment to the plasma membrane, Akt is activated by phosphorylation5 and then phosphorylates numerous protein targets. Akt can be inactivated by the actions of protein phosphatase 2A (PP2A).6 The Akt-activating ability of PI3-K is opposed by the lipid phosphatase PTEN.7 PTEN was first described as a tumor suppressor located on chromosome 10q23, which is commonly deleted in brain, breast, and prostate cancers.8-10
Together, constitutive activation of Akt, chromosomal amplification of Akt or PI3-K, or PTEN deletion seem to be selected during tumor formation in a wide variety of tissues, and play a role in the tumorigenic process. The original description of Akt involved virally induced carcinogenesis resulting from a constitutively active form of Akt.11 Likewise, PI3-K has been found to act as a viral oncoprotein.12 The initial description of Akt also identified amplification of its sequence in some gastric adenocarcinomas,13 and amplifications of both Akt14 and of PI3-K15 have now been observed in other solid tumors. Although these events highlight the importance of activation of the PI3-K/Akt pathway as a mechanism for transformation, by far the most frequently mutated component of this pathway is the tumor suppressor PTEN. Mutations in the PTEN sequence occur at high frequency in several tumor types, including 83% of endometrial carcinomas16 and 34% of glioblastomas.17 A review of 54 separate reports examining a total of 2,285 tumor specimens found an average mutation rate of 16% across many tumor types, including melanoma as well as prostate, head and neck, and renal cell carcinomas.18 Many transforming events that do not result in direct genetic modification of PI3-K, Akt, or PTEN still cause activation of the PI3-K/Akt/PTEN pathway. Three examples of such transforming events are the BCR/ABL translocation, which is the causative event in chronic myelogenous leukemia, amplification of HER-2/neu seen frequently in primary breast carcinomas, and amplification of the epidermal growth factor receptor (EGFR) seen in multiple carcinomas.
BCR/ABL and Imatinib
HER-2/neu and Trastuzumab Many of the transforming events mediated by overexpression of the HER-2/neu tyrosine kinase are the result of enhanced signaling through the PI3-K/Akt pathway29,30 (Fig 1). Furthermore, interruption of signaling through Akt was shown to be essential for the cytotoxic effect of trastuzumab: breast carcinoma cell lines that were formerly sensitive to this agent in vitro become resistant after transfection with a constitutively active Akt transgene.31
EGFR and Its Inhibitors The aberrant activation of these three tyrosine kinases highlights the importance of the activation of the PI3-K/Akt/PTEN pathway in the establishment of malignant transformation. These examples demonstrate a common mechanism of resistance to chemotherapy: a profound resistance to apoptosis. When Akt is inhibited, malignant cells lose their resistance to apoptosis; the importance of this effect is demonstrated by experiments in which apoptotic resistance is restored, and drug effects lost, when cells are transfected with a constitutively active form of Akt. This mechanism of action has important implications for the use of agents targeting Akt as monotherapy, as will be discussed further at the conclusion of this review.
The regulation of the activation and deactivation of Akt's protein kinase activity involves the complex interaction of lipid kinases, protein kinases, lipid phosphatases, and protein phosphatases. These interactions maintain tight control over the activity of this essential regulator of apoptosis, as evidenced by the transforming properties of overexpressed PI3-K and Akt, and the tumor suppressor activity of PTEN. These pathways may thus represent additional targets for new therapeutics in tumors dependent on the PI3-K/Akt/PTEN pathway.
PI3-K
PTEN An additional lipid phosphatase that may act in the PI-3K/Akt/PTEN pathway, at least in hematopoietic cells, is the enzyme Sh2-containing inositol phosphatase (SHIP),56 which acts as a D5 phosphatase and specifically dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (3,4)-bisphosphate. Mice with homozygous deletion of SHIP demonstrate myeloid hyperplasia with impaired apoptosis of neutrophils.57,58
Akt
Akt Activation Through Phosphorylation
Inactivation of Akt by Dephosphorylation
Maintenance of normal tissue morphology and function is dependent on the availability of survival factors.69-71 Recent studies suggest that Akt plays an essential antiapoptotic role in survival signal transduction. Although there is some overlap with mitogenesis, the signaling pathways for survival have been shown to be distinct from those for cell growth and cell division. The first report of a signaling pathway that specifically mediates survival demonstrated that nerve growth factor-mediated survival of a neuronal cell line requires activation of PI3-K but not Ras.72 Subsequent studies extended these results to additional cell lines and survival factors.73,74 The PI3-K survival signal was then shown to be mediated by Akt in numerous experimental systems75-79 (Fig 1).
Proposed Mechanisms for Akt-Mediated Apoptotic Resistance
None of the above mechanisms completely account for Akt's effects on apoptosis. Akt has been shown to protect cells from apoptosis without new protein synthesis,94,95 which makes it unlikely that changes in transcription from the NF-  B or forkhead transcription factors are essential to its antiapoptotic function. Likewise, recent studies have indicated that phosphorylation of Bad does not correlate with inhibition of apoptosis,96 and no phenotype has been reported for targeted mutation of this gene in mice. These observations have prompted the exploration of alternative mechanisms for the antiapoptotic function of Akt.
Akt Is a Direct Regulator of Glucose Metabolism Glucose cannot easily diffuse through biologic membranes, and thus must pass through facilitative transporters at the cell surface (Fig 2). The level of transporters on the cell surface is regulated both at the level of transcription and through segregation of the transporters in cytoplasmic vesicles. Constitutively active forms of Akt have been shown to stimulate both of these processes.95,98 After diffusion into a cell through facilitative transport, glucose is converted to glucose-6-phosphate by hexokinase, preventing diffusion out of the cell through the bidirectional transporters.99 Thus, the activity of hexokinase exerts a profound effect on the overall rate of glucose uptake, and activated forms of Akt have been shown to stimulate hexokinase activity.94,95 Although phosphorylation of glucose traps it in a cell, it is not committed to glycolysis until converted through fructose 6-phosphate to fructose 1,6-bisphosphate.99 The final, and essentially irreversible, step of this conversion is performed by phosphofructokinase (PFK-1). As this enzyme controls the commitment of glucose to energy production, it is allosterically inhibited by high adenosine triphosphate levels. This inhibition can be overcome by another allosteric regulator of PFK-1, fructose 2,6-bisphosphate, which is generated by the activity of PFK-2.100 Akt has been shown to phosphorylate and activate PFK-2.101
Although these Akt-dependent effects are essential to insulin's ability to stimulate glucose uptake and metabolism in insulin-responsive tissues such as muscle or fat, Akt's role in glucose metabolism and its influence on cell survival in other cell types has only recently been explored.
The role of glucose metabolism in carcinogenesis has been controversial. Otto Warburg determined nearly 80 years ago that a hallmark of transformation is an enhancement in glycolytic metabolism despite the presence of oxygen, a phenomenon now called the Warburg effect.102 Although these and other investigations won him the Nobel prize in 1931, Warburg insisted throughout his career that his findings indicated that a defect in the mechanics of oxidative phosphorylation was the causative event in most cancers.103 This conclusion has been the subject of considerable controversy over the years.104
Positron Emission Tomography Scanning Detects High Glucose Uptake
The Role of Mitochondria in Apoptosis May Link Glucose Metabolism to Cell Death
PET Positivity Is Not Confined to Aggressive Lymphomas
Oncogenic Akt Can Lead to Direct Stimulation of Glycolysis in Lymphocytes
The serine-threonine kinase mammalian target of rapamycin (mTOR) is a downstream target of Akt that may be responsible for Akt's effects on nutrient transport.116 Akt can directly phosphorylate mTOR,117 but it is unclear if activation of the mTOR kinase by activated Akt is caused by direct phosphorylation118 or indirectly by inactivation of the tumor suppressor tuberin.119,120 The TOR kinases were first discovered in yeast when point mutations in these genes rendered the yeast resistant to the macrolide antimycotic agent rapamycin.121 In yeast the TOR kinases function to regulate nutrient transporter expression in response to nutrient availability.122 The mammalian homolog of these kinases, termed mTOR, has been shown to serve similar functions.123 In addition to the effects on glucose uptake described above, withdrawal of growth factor also results in diminished uptake of other nutrients essential to cell growth, including amino acids, transferrin, and low-density lipoprotein–cholesterol, and these effects can also be attenuated by a constitutively active Akt.124 The maintenance of nutrient uptake by Akt is eliminated in the presence of rapamycin,124 suggesting that mTOR is necessary for these effects. In addition to these effects on nutrient uptake, treatment of cells with rapamycin markedly diminished the ability of a constitutively active Akt to suppress apoptosis.124 Rapamycin-dependent effects on apoptosis have been demonstrated in other cell systems,125,126 but the precise mechanism of this effect remains to be established. One report has demonstrated that the p70 ribosomal S6 kinase, which is a major effector downstream of mTOR, can phosphorylate Bad.127 Several preclinical studies have indicated that rapamycin or its derivatives specifically inhibit the transforming effect of the PI3-K/Akt pathway. For example, rapamycin inhibits the transforming activity of the oncogenic variants of PI3-K and Akt, but does not similarly inhibit several oncoproteins, including v-Jun and v-Src.128 In a preclinical breast carcinoma evaluation of a parenteral rapamycin analog, CCI-779, only those cell lines that demonstrated growth factor dependence (presence of the estrogen receptor), HER-2/neu overexpression, and/or loss of PTEN were sensitive to the drug, despite evidence of inhibition of mTOR activity in the resistant cell lines.129 In addition, these agents seem to have particular promise for tumors that lack functional PTEN, given that treatment of Pten +/– mice with CCI-779 reduced the growth of the characteristic uterine and adrenal tumors seen in these mice.130 There are now several clinical trials of rapamycin derivatives, with CCI-779 now in phase II trials in renal cell, breast, and prostate carcinomas.
Although the inhibition of the PI3-K/Akt pathway has been demonstrated to induce apoptosis in experimental models, the goal of an effective clinical agent would be to allow the eradication of most or, ideally, all neoplastic cells in the patient receiving the drug. Unfortunately, inhibition of Akt's function may not prove cytotoxic in all situations. Cells that are not undergoing cellular stress, and thus less are dependent on protection from apoptosis through the PI3-K/Akt pathway, may be able to survive temporary inhibition of this pathway. This would be of the utmost importance in the design of trials of new agents targeted to the PI3-K/Akt pathway, given that they would be expected to augment the effect of more conventional chemotherapeutic agents by removing the shield used by transformed cells to avoid apoptosis. Akt is involved in the neoplastic transformation of many tumors, either through direct amplification or, more commonly, through loss of the inhibitory effect of PTEN. Once activated, Akt plays an essential role in maintaining the viability of these neoplastic cells, through direct inhibition of proapoptotic molecules, induction of antiapoptotic molecules, and maintenance of normal cellular metabolism in otherwise unfavorable conditions. Inhibition of the Akt pathway, either through inhibitors of downstream elements such as mTOR or through more direct effects on improving the function of PTEN or inhibiting that of PI3-K/Akt, may prove highly effective in future treatment regimens, though likely in combination with traditional agents. Imaging modalities directed at an enhanced glycolytic rate, which can be induced by Akt, have already borne fruit with the expanding use of PET imaging for diagnosis and staging of a number of malignancies.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Craig B. Thompson, Abbott Lab, Xcyte Therapies, IDUN Pharmaceuticals. Received more than $2,000 a year from a company for either of the last 2 years: Craig B. Thompson, Abbott Lab, Xcyte Therapies, IDUN Pharmaceuticals.
We thank Tracy S. d'Entremont, MD, Alison W. Loren, MD, Sarah G. Thompson, MD, and M. Luisa Veronese, MD for numerous helpful comments.
J.E.T. was supported by National Institutes of Health grants T32-HL07439-24 and K08-HL73977-01. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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