PI 3-kinase and cancer: changing accents

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Research on PI 3-kinase (PI3K) is undergoing significant shifts in emphasis. Questions that have been dormant for some time are coming to the forefront, such as the relationship of PTEN to PI3K and the role of AKT in PI3K-driven oncogenesis. Two non-alpha isoforms of Class I PI3K are now established as important determinants in cancer: p110β and p110δ. The oncogenic activities of p110β include a non-catalytic function, a finding that will have immediate consequences for drug development.

Introduction

The PI 3-kinase (PI3K) field has entered a phase of rapid and dynamic development. Although the basics remain unchanged, there are significant shifts in accents and emphasis. This is particularly true of Class I PI3K which has great significance for cancer and which will be the subject of this review. Among the questions that have recently come under scrutiny is the role of AKT (murine thymoma viral oncoprotein homolog) in the oncogenic signals from PI3K and the relationship between loss of PTEN (phosphatase and tensin homolog) and activation of PI3K. The non-alpha isoforms of Class I p110 are shedding their tentative and subordinate roles in oncogenesis and are emerging as important factors in cancer. In this paper, we will discuss questions that are raised by these recent developments.

PI3K was initially linked to cancer in studies of oncogenic viruses. The middle T antigen of polyoma virus, the Src oncoprotein of Rous sarcoma virus and the Ros oncoprotein of the avian sarcoma virus UR2 are associated with PI3K activity [1, 2, 3]. More direct evidence for the oncogenic potential of PI3K comes from avian sarcoma virus 16 which carries a homolog of the PIK3CA gene, coding for p110α, the catalytic subunit of PI3K, as its tumorigenic determinant [4]. In human cancer, deregulation of the PI3K signaling pathway has been recorded with increasing frequency, caused by gain of function in receptor tyrosine kinases, amplification of PIK3CA, activation of the serine-threonine kinase AKT or loss of function of the tumor suppressor phosphatase PTEN that is the catalytic antagonist of PI3K [5, 6, 7, 8]. But it was the discovery of cancer-specific mutations in PIK3CA that moved PI3K into the limelight [9]. These mutations confer a gain of function as measured by enzymatic activity, constitutive downstream signaling and oncogenic potential [10, 11, 12••, 13, 14, 15]. About 80% of the mutations occur in three hot spots in the gene, each represented by a single nucleotide substitution. The existence of these hot spots strongly suggests that the mutations provide a replicative advantage to the cell which is in accord with the gain of function detected by diverse assays of activity [9]. The mutant p110α proteins would appear as ideal therapeutic targets: they are restricted to cancer cells and, as enzymes, are readily controllable by small-molecule compounds, but mutant-specific inhibitors have not yet been generated [16].

Section snippets

Mutants and mechanisms

The mutant p110α proteins have raised the question of the molecular mechanisms that are responsible for the gain of function. Definitive answers to this question must await specific structural information on the mutants. Genetic experiments suggest the existence of several such mechanisms. Thus, combining kinase domain and helical domain hot spot mutations in the same molecule has a strong synergistic effect on signaling and oncogenicity. Kinase and helical domain mutations also differ in their

PI3K, PTEN and AKT: questions of correlations and connections

Figure 1 presents basic elements of PI3K signaling from upstream input by activated receptor tyrosine kinases or G-protein-coupled receptors to one of the major downstream targets, the TOR (target of rapamycin) kinase. Although didactically useful, such simplistic renderings could inadvertently lead to incorrect assumptions. For instance, on paper, a loss of function in PTEN is equivalent to a gain of function in PI3K, as both lead to increased levels of PIP3 which are regarded as the

The non-alpha isoforms of Class I p110: emerging roles in cancer

Class I PI3K contains four p110 isoforms, α, β, γ and δ. The association between p110α and cancer is well established and has been greatly strengthened by the occurrence of gain of function p110α mutations in human cancer [9]. The relationship of the non-alpha isoforms to cancer and their possible role as oncogenes has been more tenuous, but recent discoveries have changed that situation. A surprising observation was made with the four p110 isoforms overexpressed in avian fibroblasts. Whereas

Conclusions

We still know far too little about the direct and indirect interactions between PTEN and PI3K and their extensive signaling networks. Recent publications have brought insights and focus to this problem [8, 23•, 24, 25••, 27, 30••]. They support the conclusion that loss of PTEN has isoform-specific consequences for PI3K, and these consequences may be cell type-specific. The entry of p110β and p110δ into the realm of cancer marks a milestone for the therapeutic potential of targeting these

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

Work of the authors is supported by grants from the National Cancer Institute and by the Stein Fund. This is manuscript number 19791 of The Scripps Research Institute.

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