Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic

Kang, Sohye; Bader, Andreas G.; Vogt, Peter K.

doi:10.1073/pnas.0408864102

Cited by 751 publications

(672 citation statements)

References 44 publications

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“…Transformation by constitutively active chicken p110a and cancer-specific mutants of p110a has been shown to involve TOR and its downstream targets, ribosomal protein S6 kinase 70 kDa polypeptide 1 (S6K) and eukaryotic initiation factor 4E binding protein (4E-BP1) (Aoki et al, 2001;Kang et al, 2005). Degradation of FoxO1 also occurs during transformation induced by the oncogenic myristylated chicken p110a (Aoki et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

“…The specific functions of the non-a class I PI3K isoforms in normal physiology suggested that the mechanism of transformation induced by these oncoproteins could be different. Oncogenic signaling of p110d and of cancer-specific mutants p110a is correlated with constitutive activation of Akt (Kang et al, 2005). However, the p110g isoform activates Akt only conditionally, whereas p110b does not mediate detectable phosphorylation of Akt (Zhao et al, 2005;Kang et al, 2006).…”

Section: Discussionmentioning

confidence: 98%

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Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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“…19,33 Activated PI3-kinase phosphorylates inositol lipids, resulting in the activation of the serine/threonine kinase PKB that phosphorylates caspase-9 and BAD, promoting cell survival. 19 Activated PKB can also regulate cellular proliferation by interaction in the nucleus with cell cycle regulators governing G1/S and G2/M checkpoints.…”

Section: Discussionmentioning

confidence: 99%

ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase

et al. 2006

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The emergence of resistance to chemotherapy remains a principle problem in the treatment of small-cell lung cancer (SCLC). We demonstrate that extracellular matrix (ECM) activates phosphatidyl inositol 3-kinase (PI3-kinase) signaling in SCLC cells and prevents etoposide-induced caspase-3 activation and subsequent apoptosis in a b1 integrin/PI3-kinase-dependent manner. Crucially we show that etoposide and radiation induce G2/M cell cycle arrest in SCLC cells prior to apoptosis and that ECM prevents this by overriding the upregulation of p21 Cip1/WAF1 and p27 Kip1 and the downregulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signaling. Importantly we show that chemoprotection is not mediated by altered SCLC cell proliferation or DNA repair. Thus, ECM via b1 integrin-mediated PI3-kinase activation overrides treatment-induced cell cycle arrest and apoptosis, allowing SCLC cells to survive with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance.

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“…PIK3CA somatic mutations are frequently associated with a variety of solid tumors including breast, colon, lung, ovarian, and gastric cancer 15, 16, 17 and they are also observed in patients with overgrowth syndromes, categorized as PROS 18. Somatic mosaic PIK3CA mutations can affect different tissues.…”

Section: Discussionmentioning

confidence: 99%

PIK3CA c.3140A>G mutation in a patient with suspected Proteus Syndrome: a case report

Valentini

Zelli

Rizzolo

et al. 2018

Clinical Case Reports

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Key Clinical MessageWe present a patient with suspected Proteus Syndrome, an overgrowth disorder associated with AKT1c.49G>A mutation. NGS analysis detected PIK3CAc.3140A>G mutation in the patient's affected tissue allowing for PROS (PIK3CA‐related overgrowth spectrum) diagnosis. The overlapping clinical features in overgrowth disorders highlight the importance of molecular testing for a correct diagnosis.

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Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic

Abstract: Akt ͉ oncogenic transformation ͉ p110␣ ͉ PIK3CA

Cited by 751 publications

References 44 publications

Oncogenic signaling of class I PI3K isoforms

Oncogenic signaling of class I PI3K isoforms

ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase

PIK3CA c.3140A>G mutation in a patient with suspected Proteus Syndrome: a case report

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