A major problem in treating oesophageal squamous cell carcinoma (ESCC) with cisplatin is the development of drug resistance. In order to determine whether phosphatidylinositol 3-kinase (PI3K)-C2β (encoded by the PIK3C2B gene) reduced the sensitivity of ESCC to cisplatin, transfected Eca109 cells that overexpressed PIK3C2B were produced. Additionally, PI3K-C2β-siRNA was used to silence endogenous PI3K-C2β in EC9706 cisplatin-resistant cells. The relationship between PIK3C2B expression and clinicopathological characteristics was also investigated in samples from 61 patients. The overexpression of PIK3C2B in Eca109 cells significantly inhibited cisplatin-induced apoptosis and cleavage of caspase-3. Knockdown of PI3K-C2β enhanced cisplatin-induced apoptosis in EC9706 cells. PIK3C2B expression was associated with an increased level of phosphorylated Akt. Based on the tumour samples, expression of PIK3C2B was associated with tumour metastasis and in vitro assay suggested that it mediated cell migration. These results indicated that PI3K-C2β, via the Akt signalling pathway, might play a key role in cisplatin resistance and that targeting this pathway might be useful in treating cisplatin-resistant tumours.
ParkinDMBrayFFerlayJ: Global cancer statistics, 2002. CA Cancer J Clin2005; 55: 74–108.
2.
PoleeMBKokTCSiersemaPD: Phase II study of the combination cisplatin, etoposide, 5-fluorouracil and folinic acid in patients with advanced squamous cell carcinoma of the esophagus. Anticancer Drugs2001; 12: 513–517.
3.
IlsonDHKelsenDP: Management of esophageal cancer. Oncology (Williston Park)1996; 10: 1385–1402.
4.
OhmichiMHayakawaJTasakaK: Mechanisms of platinum drug resistance. Trends Pharmacol Sci2005; 26: 113–116.
5.
ChuG: Cellular responses to cisplatin. The roles of DNA-binding proteins and DNA repair. J Biol Chem1994; 269: 787–790.
6.
KellandLR: A new resistance mechanism to cisplatin?Drug Resist Updat2000; 3: 139–141.
BarryMABehnkeCAEastmanA: Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol1990; 40: 2353–2362.
9.
FrankeTFHornikCPSegevL: PI3K/Akt and apoptosis: size matters. Oncogene2003; 22: 8983–8998.
10.
YangXFraserMAbediniMR: Regulation of apoptosis-inducing factor-mediated, cisplatin-induced apoptosis by Akt. Br J Cancer2008; 98: 803–808.
11.
EngelmanJA: Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer2009; 9: 550–562.
12.
HayakawaJOhmichiMKurachiH: Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin. Cancer Res2000; 60: 5988–5994.
13.
TranHBrunetAGrenierJM: DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science2002; 296: 530–534.
14.
KimuraAOhmichiMKawagoeJ: Induction of hTERT expression and phosphorylation by estrogen via Akt cascade in human ovarian cancer cell lines. Oncogene2004; 23: 4505–4515.
15.
MabuchiSOhmichiMNishioY: Inhibition of NFκB increases the efficacy of cisplatin in in vitro and in vivo ovarian cancer models. J Biol Chem2004; 279: 23477–23485.
16.
WheelerMDominJ: The N-terminus of phosphoinositide 3-kinase-C2β regulates lipid kinase activity and binding to clathrin. J Cell Physiol2006; 206: 586–593.
17.
MaffucciTCookeFFosterFM: Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. J Cell Biol2005; 169: 789–799.
18.
DominJHarperLAubynD: The class II phosphoinositide 3-kinase PI3K-C2β regulates cell migration by a PtdIns3P dependent mechanism. J Cell Physiol2005; 205: 452–462.
19.
DasMScappiniEMartinNP: Regulation of neuron survival through an intersectinphosphoinositide 3′-kinase C2β-AKT pathway. Mol Cell Biol2007; 27: 7906–7917.
20.
ElisWTriantafellowEWoltersNM: Down-regulation of class II phosphoinositide 3-kinase α expression below a critical threshold induces apoptotic cell death. Mol Cancer Res2008; 6: 614–623.
21.
BrunetADattaSRGreenbergME: Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol2001; 11: 297–305.
22.
DominJPagesFVoliniaS: Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem J1997; 326: 139–147.
23.
VišnjićDCrljenVCurićJ: The activation of nuclear phosphoinositide 3-kinase C2β in all-trans-retinoic acid-differentiated HL-60 cells. FEBS Lett2002; 529: 268–274.
24.
El SheikhSSDominJTomtitchongP: Topographical expression of class IA and class II phosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation. BMC Clin Pathol2003; 3: 4.
25.
MarrasEConcariPCortellezziL: Involvement of PI3K in PKCε-mediated oncogenic signal in rat colonic epithelial cells. Int J Oncol2001; 19: 395–399.
26.
TraerCJFosterFMAbrahamSM: Are class II phosphoinositide 3-kinases potential targets for anticancer therapies?Bull Cancer2006; 93: E53–E58.
27.
KangSSongJKangJ: Suppression of the α-isoform of class II phosphoinositide 3-kinase gene expression leads to apoptotic cell death. Biochem Biophys Res Commun2005; 329: 6–10.
28.
SatoNFukushimaNMaitraA: Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreas. Am J Pathol2004; 164: 903–914.
29.
ArmstrongSAStauntonJESilvermanLB: MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet2002; 30: 41–47.
30.
Rodriguez-VicianaPWarnePHKhwajaA: Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell1997; 89: 457–467.
31.
ArcaroAVoliniaSZvelebilMJ: Human phosphoinositide 3-kinase C2β, the role of calcium and the C2 domain in enzyme activity. J Biol Chem1998; 273: 33082–33090.
32.
KatsoRMPardoOEPalamidessiA: Phosphoinositide 3-kinase C2β regulates cytoskeletal organization and cell migration via Rac-dependent mechanisms. Mol Biol Cell2006; 17: 3729–3744.
33.
El ArafaSAZhuQBarakatBM: Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway. Cancer Res2009; 69: 8910–8917.
34.
TsaiWSYeowWSChuaA: Enhancement of Apo2L/TRAIL-mediated cytotoxicity in esophageal cancer cells by cisplatin. Mol Cancer Ther2006; 5: 2977–2990.
35.
ChengJQJiangXFraserM: Role of X-linked inhibitor of apoptosis protein in chemoresistance in ovarian cancer: possible involvement of the phosphoinositide-3 kinase/Akt pathway. Drug Resist Updat2002; 5: 131–146.
36.
WuHCaoYWengD: Effect of tumor suppressor gene PTEN on the resistance to cisplatin in human ovarian cancer cell lines and related mechanisms. Cancer Lett2008; 271: 260–271.
37.
GajewskiTFThompsonCB: Apoptosis meets signal transduction: elimination of a BAD influence. Cell1996; 87: 589–592.
