The Opposing Roles of PIK3R1/p85α and PIK3R2/p85β in Cancer
2019; Elsevier BV; Volume: 5; Issue: 4 Linguagem: Inglês
10.1016/j.trecan.2019.02.009
ISSN2405-8033
AutoresJesús Vallejo-Díaz, Mónica Chagoyen, Manuel Olazabal-Morán, Ana González‐García, Ana C. Carrera,
Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoThe Cancer Genome Atlas Project revealed that specific changes in gene expression are hallmarks of some cancers. Expression of PIK3R2, encoding the p85β regulatory subunit of PI3K, increases with advanced tumor stage in melanoma, breast, and squamous cell lung carcinoma. Pik3r2 overexpression induces metastasis in mouse models, whereas preclinical deletion of PIK3R2 induces tumor regression and reduces invasion. PIK3R1/p85α has a tumor-suppressor function, whereas PIK3R2/p85β is a tumor driver. Understanding why these subunits play opposing roles in tumor development will be important to design better therapies. Dysregulation of the PI3K/PTEN pathway is a frequent event in cancer, and PIK3CA and PTEN are the most commonly mutated genes after TP53. PIK3R1 is the predominant regulatory isoform of PI3K. PIK3R2 is an ubiquitous isoform that has been so far overlooked, but data from The Cancer Genome Atlas shows that increased expression of PIK3R2 is also frequent in cancer. In contrast to PIK3R1, which is a tumor-suppressor gene, PIK3R2 is an oncogene. We review here the opposing roles of PIK3R1 and PIK3R2 in cancer, the regulatory mechanisms that control PIK3R2 expression, and emerging therapeutic approaches targeting PIK3R2. Dysregulation of the PI3K/PTEN pathway is a frequent event in cancer, and PIK3CA and PTEN are the most commonly mutated genes after TP53. PIK3R1 is the predominant regulatory isoform of PI3K. PIK3R2 is an ubiquitous isoform that has been so far overlooked, but data from The Cancer Genome Atlas shows that increased expression of PIK3R2 is also frequent in cancer. In contrast to PIK3R1, which is a tumor-suppressor gene, PIK3R2 is an oncogene. We review here the opposing roles of PIK3R1 and PIK3R2 in cancer, the regulatory mechanisms that control PIK3R2 expression, and emerging therapeutic approaches targeting PIK3R2. PI3K enzymes are a conserved family of lipid kinases that phosphorylate the inositol 3′-OH groups of membrane phosphoinositides (PI). Class I PI3K enzymes convert PI(4,5)bisphosphate (PIP2) into PI(3,4,5)trisphosphate (PIP3), a second messenger. Class IA PI3K is composed of a heterodimer between a p110 catalytic subunit and a p85 regulatory subunit. Of the four PI3K catalytic subunit isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), only PI3Kα and PI3Kβ are expressed ubiquitously and are frequently altered in cancer [1Hirsch E. et al.PI3 K in cancer–stroma interactions: bad in seed and ugly in soil.Oncogene. 2014; 33: 3083-3090Crossref PubMed Scopus (52) Google Scholar, 2Vanhaesebroeck B. et al.PI3K: from the bench to the clinic and back.Curr. Top. Microbiol. Immunol. 2010; 347: 1-19PubMed Google Scholar]. Three different genes encode p85-type subunits: PIK3R1, PIK3R2, and PIK3R3, and these code for p85α (and alternative splice forms), p85β and p55γ, respectively. PIK3R1 and PIK3R2 are broadly expressed, whereas PIK3R3 is selectively expressed in adult testis and the brain [1Hirsch E. et al.PI3 K in cancer–stroma interactions: bad in seed and ugly in soil.Oncogene. 2014; 33: 3083-3090Crossref PubMed Scopus (52) Google Scholar, 2Vanhaesebroeck B. et al.PI3K: from the bench to the clinic and back.Curr. Top. Microbiol. Immunol. 2010; 347: 1-19PubMed Google Scholar, 3Ueki K. et al.Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85alpha regulatory subunit.Mol. Cell Biol. 2000; 20: 8035-8046Crossref PubMed Scopus (127) Google Scholar, 4Fruman D.A. Regulatory subunits of class IA PI3K.Curr. Top. Microbiol. Immunol. 2010; 346: 225-244PubMed Google Scholar]. PIK3R1/p85α is the most abundant isoform in normal tissues [5Ueki K. et al.Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival.Mol. Cell Biol. 2002; 22: 965-977Crossref PubMed Scopus (218) Google Scholar, 6Alcázar I. et al.p85β phosphoinositide 3-kinase regulates CD28 co-receptor function.Blood. 2009; 113: 3198-3208Crossref PubMed Scopus (29) Google Scholar, 7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar] but its expression is reduced in cancer. Conversely, PIK3R2/p85β expression levels are elevated in advanced cancer stages ([7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar, 8Sun M. et al.Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 15547-15552Crossref PubMed Scopus (124) Google Scholar]; data from The Cancer Genome Atlas, TCGAi). Physiological activation of PI3K is induced by binding of p85 to activated receptor tyrosine kinases (RTKs) and is further enhanced by GTPases of the Ras family. Rho GTPases and G protein-coupled receptors also activate PI3Kβ [1Hirsch E. et al.PI3 K in cancer–stroma interactions: bad in seed and ugly in soil.Oncogene. 2014; 33: 3083-3090Crossref PubMed Scopus (52) Google Scholar, 2Vanhaesebroeck B. et al.PI3K: from the bench to the clinic and back.Curr. Top. Microbiol. Immunol. 2010; 347: 1-19PubMed Google Scholar, 9Dbouk H.A. et al.G protein-coupled receptor-mediated activation of p110β by Gβγ is required for cellular transformation and invasiveness.Sci. Signal. 2012; 5ra89Crossref PubMed Scopus (106) Google Scholar, 10Fritsch R. et al.RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms.Cell. 2013; 153: 1050-1063Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar]. Classically, p85α and p85β have been considered to be similar proteins that associate with RTKs and with catalytic subunits that induce PI3K activation. This may represent an oversimplification because a growing number of studies support different and opposite functions of p85α and p85β in cancer [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar, 8Sun M. et al.Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 15547-15552Crossref PubMed Scopus (124) Google Scholar]. In this review article we summarize available data on the function p85α and p85β, and attempt to make sense of the observation that PIK3R1 and PIK3R2 have opposing functions in tumor progression. This is important because distinct consequences of interfering with PIK3R1/p85α or PIK3R2/p85β should be considered in the design and development on new therapies. p85 subunits control PI3K activation by modulating the stability, conformation, and localization of the catalytic subunit [4Fruman D.A. Regulatory subunits of class IA PI3K.Curr. Top. Microbiol. Immunol. 2010; 346: 225-244PubMed Google Scholar, 11Yu J. et al.Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.Mol. Cell Biol. 1998; 18: 1379-1387Crossref PubMed Google Scholar, 12Burke J.E. Structural basis for regulation of phosphoinositide kinases and their involvement in human disease.Mol. Cell. 2018; 71: 653-673Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar]. The primary structure of p85 includes an N-terminal region composed of an Src homology 3 (SH3) domain followed by a RhoGap homology region located between two proline-rich domains (scheme in Figure 1A). At the C-terminal region, two Src homology 2 (SH2) regions, separated by the so-called inter-SH2 region (i-SH2), mediate the binding of p85 to the catalytic subunit [11Yu J. et al.Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.Mol. Cell Biol. 1998; 18: 1379-1387Crossref PubMed Google Scholar, 12Burke J.E. Structural basis for regulation of phosphoinositide kinases and their involvement in human disease.Mol. Cell. 2018; 71: 653-673Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar]. The domain organization of p85β is similar to that of p85α, and sequence comparison shows that they are highly homologous in the C-terminal region (nSH2–i-SH2–cSH2 domains) but only 37% identical in their N-terminal regions (Figure 1A). p85α firmly binds to the p110 catalytic subunit, and this increases its stability and restrains its catalytic activity [11Yu J. et al.Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.Mol. Cell Biol. 1998; 18: 1379-1387Crossref PubMed Google Scholar]. Upon binding to activated RTK, the SH2 domains mediate translocation of PI3K to the plasma membrane and trigger a conformational change that contributes to its activation [12Burke J.E. Structural basis for regulation of phosphoinositide kinases and their involvement in human disease.Mol. Cell. 2018; 71: 653-673Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar]. These features have been studied in depth for p85α, but the high degree of identity in the C-terminal region supports the idea that p85β acts similarly. In interphase, p85α and p85β have different intracellular distributions. Whereas p85α localizes mainly to internal cell membranes, including the Golgi apparatus [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar, 13Luo J. et al.The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex.J. Cell Biol. 2005; 170: 455-464Crossref PubMed Scopus (122) Google Scholar], a fraction of p85β localizes to the cytosol, and also concentrates at focal adhesions as well as in the nucleus [14Cariaga-Martínez A.E. et al.Phosphoinositide 3-kinase p85beta regulates invadopodium formation.Biol. Open. 2014; 3: 924-936Crossref PubMed Scopus (15) Google Scholar, 15Kumar A. et al.Nuclear but not cytosolic phosphoinositide 3-kinase beta has an essential function in cell survival.Mol. Cell Biol. 2011; 31: 2122-2133Crossref PubMed Scopus (64) Google Scholar]. p85β localization at focal adhesions contributes to its oncogenic role (see below). In the nucleus, p85β associates with PI3Kβ and is required for PI3Kβ nuclear function [16Kumar A. et al.Nuclear phosphoinositide 3-kinase beta controls double-strand break DNA repair.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 7491-7496Crossref PubMed Scopus (130) Google Scholar]. In addition to the aforementioned differences, studies performed with purified p85α or p85β in combination with p110 revealed that p85β/p110 has greater affinity than p85α/p110 for the physiological PI3K substrate, PIP2. In addition, in quiescent cells p85α exerts a greater control on basal p110/PI3K activity than does p85β (Box 1).Box 1In Vitro and In Vivo Functions of PIK3R1 and PIK3R2Comparative assays performed with immune-purified p85α/p110α and p85β/p110α showed that p85α/p110α has greater activity towards PIP, the precursor to PI(3)P-, whereas p85β/p110α is more active than p85α/p110α against the physiological substrate, PIP2 [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar]. p85α and p85β also behave differently in cells. For instance, overexpression of p85α, but not of p85β, impairs basal Akt activity [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar]. Although addition of growth factors results in enhanced PIP3 levels in both p85α/p110α- and p85β/p110α-expressing cells, in the absence of a stimulus only p85β/p110α-expressing cells exhibit basal PI3K activity [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar]. These results support the notion that p85α blocks p110 activity more efficiently than does p85β.In mice, p85α and p85β show partial redundancy. Indeed, although embryonic development is not altered in mice lacking either Pik3r1 or Pik3r2, the double-mutant mice showed embryonic lethality at day 12.5 [65Brachmann S.M. et al.Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement.Mol. Cell Biol. 2005; 25: 2593-2606Crossref PubMed Scopus (106) Google Scholar]. Pik3r1-deficient mice die perinatally, and exhibit extensive hepatocyte necrosis as well as defective glucose homeostasis and B cell development [17Fruman D.A. et al.Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha.Science. 1999; 283: 393-397Crossref PubMed Scopus (571) Google Scholar, 66Fruman D.A. et al.Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha.Nat. Genet. 2000; 26: 379-382Crossref PubMed Scopus (252) Google Scholar, 67Terauchi Y. et al.Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase.Nat. Genet. 1999; 21: 230-235Crossref PubMed Scopus (346) Google Scholar]. By contrast, Pik3r2 knockout mice are born and grow normally, as if p85β were dispensable for the homeostasis of most normal cells; Pik3r2-deficient mice only show moderately enhanced T and B cell responses and defective acquisition of long-lived memory cells [6Alcázar I. et al.p85β phosphoinositide 3-kinase regulates CD28 co-receptor function.Blood. 2009; 113: 3198-3208Crossref PubMed Scopus (29) Google Scholar, 63Deane J.A. et al.Enhanced T cell proliferation in mice lacking the p85beta subunit of phosphoinositide 3-kinase.J. Immunol. 2004; 172: 6615-6625Crossref PubMed Scopus (53) Google Scholar, 64Oak J.S. et al.The p85beta regulatory subunit of phosphoinositide 3-kinase has unique and redundant functions in B cells.Autoimmunity. 2009; 42: 447-458Crossref PubMed Scopus (15) Google Scholar]. These observations support the distinct functions of p85α and p85β. Comparative assays performed with immune-purified p85α/p110α and p85β/p110α showed that p85α/p110α has greater activity towards PIP, the precursor to PI(3)P-, whereas p85β/p110α is more active than p85α/p110α against the physiological substrate, PIP2 [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar]. p85α and p85β also behave differently in cells. For instance, overexpression of p85α, but not of p85β, impairs basal Akt activity [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar]. Although addition of growth factors results in enhanced PIP3 levels in both p85α/p110α- and p85β/p110α-expressing cells, in the absence of a stimulus only p85β/p110α-expressing cells exhibit basal PI3K activity [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar]. These results support the notion that p85α blocks p110 activity more efficiently than does p85β. In mice, p85α and p85β show partial redundancy. Indeed, although embryonic development is not altered in mice lacking either Pik3r1 or Pik3r2, the double-mutant mice showed embryonic lethality at day 12.5 [65Brachmann S.M. et al.Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement.Mol. Cell Biol. 2005; 25: 2593-2606Crossref PubMed Scopus (106) Google Scholar]. Pik3r1-deficient mice die perinatally, and exhibit extensive hepatocyte necrosis as well as defective glucose homeostasis and B cell development [17Fruman D.A. et al.Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha.Science. 1999; 283: 393-397Crossref PubMed Scopus (571) Google Scholar, 66Fruman D.A. et al.Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha.Nat. Genet. 2000; 26: 379-382Crossref PubMed Scopus (252) Google Scholar, 67Terauchi Y. et al.Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase.Nat. Genet. 1999; 21: 230-235Crossref PubMed Scopus (346) Google Scholar]. By contrast, Pik3r2 knockout mice are born and grow normally, as if p85β were dispensable for the homeostasis of most normal cells; Pik3r2-deficient mice only show moderately enhanced T and B cell responses and defective acquisition of long-lived memory cells [6Alcázar I. et al.p85β phosphoinositide 3-kinase regulates CD28 co-receptor function.Blood. 2009; 113: 3198-3208Crossref PubMed Scopus (29) Google Scholar, 63Deane J.A. et al.Enhanced T cell proliferation in mice lacking the p85beta subunit of phosphoinositide 3-kinase.J. Immunol. 2004; 172: 6615-6625Crossref PubMed Scopus (53) Google Scholar, 64Oak J.S. et al.The p85beta regulatory subunit of phosphoinositide 3-kinase has unique and redundant functions in B cells.Autoimmunity. 2009; 42: 447-458Crossref PubMed Scopus (15) Google Scholar]. These observations support the distinct functions of p85α and p85β. The most striking difference between p85α and p85β is observed in cancer. Whereas PIK3R1/p85α acts as a tumor suppressor, PIK3R2/p85β drives cancer. The finding that the p85α subunit restrains the catalytic activity of PI3K [11Yu J. et al.Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.Mol. Cell Biol. 1998; 18: 1379-1387Crossref PubMed Google Scholar] encouraged testing the consequences of reducing p85α levels. Because complete loss of Pik3r1 impairs mouse survival [17Fruman D.A. et al.Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha.Science. 1999; 283: 393-397Crossref PubMed Scopus (571) Google Scholar], Pik3r1 heterozygous mice were crossed with Pten heterozygous mice [18Luo J. et al.Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/− mice by the p85 regulatory subunits of phosphoinositide 3-kinase.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10238-10243Crossref PubMed Scopus (42) Google Scholar]. Pten+/− mice develop tumors in different organs as well as lymphoid and colonic hyperplasia [19Suzuki A. et al.High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice.Curr. Biol. 1998; 8: 1169-1178Abstract Full Text Full Text PDF PubMed Scopus (698) Google Scholar, 20Podsypanina K. et al.Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems.Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 1563-1568Crossref PubMed Scopus (834) Google Scholar, 21Di Cristofano A. et al.Impaired Fas response and autoimmunity in Pten+/− mice.Science. 1999; 285: 2122-2125Crossref PubMed Scopus (480) Google Scholar]. Hemizygous deletion of Pik3r1, but not of Pik3r2, increased the number of colonic polyps in Pten+/− mice [18Luo J. et al.Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/− mice by the p85 regulatory subunits of phosphoinositide 3-kinase.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10238-10243Crossref PubMed Scopus (42) Google Scholar]. By contrast, Pik3r1 partial deletion had no effect on prostate neoplasia, whereas Pik3r2 hemizygous mice showed reduced cell proliferation in the prostate [18Luo J. et al.Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/− mice by the p85 regulatory subunits of phosphoinositide 3-kinase.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 10238-10243Crossref PubMed Scopus (42) Google Scholar], supporting the idea that p85α acts as a tumor brake whereas p85β enhances tumor cell growth. In a second model, deletion of Pik3r1 in the liver led to a gradual change in hepatocyte morphology and, over time, mice developed hepatocellular carcinoma [22Taniguchi C.M. et al.The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling.Cancer Res. 2010; 70: 5305-5315Crossref PubMed Scopus (121) Google Scholar]. These observations confirm that Pik3r1 deletion induces tumor development, as expected for a tumor suppressor. Accordingly, Pik3r1 loss in mouse accelerates HER2/neu-induced mammary cancer development [23Thorpe L.M. et al.PI3K–p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K–p85α.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 7095-7100Crossref PubMed Scopus (57) Google Scholar]. PIK3R1 knockdown transforms cultured human epithelial cells, and PIK3R1 hemizygous deletion is a frequent event in breast cancer samples [23Thorpe L.M. et al.PI3K–p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K–p85α.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 7095-7100Crossref PubMed Scopus (57) Google Scholar]. Overall, these findings indicate that p85α acts as a tumor suppressor because it is capable of maintaining p110α in an inactive conformation. Accordingly, several PIK3R1 mutations in cancer samples concentrate in the i-SH2 region (Figure 1A), and the mutant p85α forms have a reduced capacity to restrain p110α [8Sun M. et al.Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.Proc. Natl. Acad. Sci. U. S. 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Similarly, one of the two hot-spot regions in PIK3CA is located at the area of interaction with p85α, and mutant forms encode a ‘relieved’ p110 form with lower stability and higher activity [27Huang C.H. et al.The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.Science. 2007; 318: 1744-1748Crossref PubMed Scopus (450) Google Scholar]. These observations confirm that the tumor-suppressor function of p85α relies on its capacity to maintain the inhibited status of PI3K until growth factor receptors are activated [8Sun M. et al.Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 15547-15552Crossref PubMed Scopus (124) Google Scholar, 23Thorpe L.M. et al.PI3K–p110α mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K–p85α.Proc. Natl. Acad. Sci. U. S. 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Somatic mutation in cancer and normal cells.Science. 2015; 349: 1483-1489Crossref PubMed Scopus (671) Google Scholar, 26Jaiswal B.S. et al.Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation.Cancer Cell. 2009; 16: 463-474Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 27Huang C.H. et al.The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.Science. 2007; 318: 1744-1748Crossref PubMed Scopus (450) Google Scholar, 28Jiménez C. et al.Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase.EMBO J. 1998; 17: 743-753Crossref PubMed Scopus (237) Google Scholar]. In agreement with the view that p85β exerts a weaker constraint on PI3K activity than does p85α, PIK3R2 has a much lower mutation rate in the area of interaction with the p110 catalytic subunit (Figure 1A) [24Cheung L.W.T. et al.High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability.Cancer Discov. 2011; 1: 170-185Crossref PubMed Scopus (345) Google Scholar]. Compared to PIK3R1 mutations, genetic alterations in PIK3R2 lead to a strikingly different phenotype. Comparative examination of p85α and p85β expression levels in a panel of colon and breast cancer samples showed that ∼50% of tumors have decreased levels of PIK3R1/p85α and increased levels of PIK3R2/p85β [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar]. This switch in regulatory subunit usage correlates with elevated Akt activation and with high-grade tumor stage; a similar correlation was also found in metastatic melanoma [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar, 14Cariaga-Martínez A.E. et al.Phosphoinositide 3-kinase p85beta regulates invadopodium formation.Biol. Open. 2014; 3: 924-936Crossref PubMed Scopus (15) Google Scholar]. In agreement with the protumoral action of PIK3R2, overexpression of p85β, but not of p85α, triggers cell transformation in culture [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. 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Examination of mRNA and protein expression levels [7Cortés I. et al.p85β phosphoinositide 3-kinase subunit regulates tumor progression.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 11318-11323Crossref PubMed Scopus (46) Google Scholar, 14Cariaga-Martínez A.E. et al.Phosphoinositide 3-kinase p85beta regulates invadopodium formation.Biol. Open. 2014; 3: 924-936Crossref PubMed Scopus (15) Google Scholar, 30Vallejo-Díaz J. et al.Targeted depletion of PIK3R2 induces regression of lung squamous cell carcinoma.Oncotarget. 2016; 7: 85063-85078Crossref PubMed Scopus (14) Google Scholar] show that increased PIK3R2/p85β expression is common in melanoma, breast, and colon cancer, as well as in lung squamous cell carcinoma (LUSC). The frequent increase in PIK3R2 expression observed in some cancer types prompted us to evaluate the consequence of depleting PIK3R2 in established tumors. 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