nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

01.01.2004 | Original Paper

Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45

verfasst von: Mitsuhiko Osaki, Satoru Kase, Keiko Adachi, Ami Takeda, Kiyoshi Hashimoto, Hisao Ito

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 1/2004

Einloggen, um Zugang zu erhalten

Abstract

It is well known that Fas ligand and anti-Fas antibodies can induce apoptosis, although some cancer cells are resistant to their stimuli. On the other hand, phosphatidylinositol 3’-kinase (PI3 K) and Akt mediate the survival signal and allow the cells to escape from apoptosis in various human cancers. Thus, we postulated that LY294002, a PI3 K inhibitor, should inactivate Akt, consequently inhibiting cell proliferation and increase apoptosis in the human gastric carcinoma cell line, MKN-45. Previously, we reported that MKN-45 was resistant against the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. LY294002 caused a decrease of phosphorylated-Akt and an inhibition of cell proliferation via cell cycle arrest in the G0/G1 phase by P27/Kip1 accumulation, but there was no obvious induction of apoptosis. The simultaneous treatment of LY294002 and CH-11 significantly induced apoptosis confirmed by morphology and DNA ladder formation. Decreased phosphorylated-Akt by LY294002 treatment led to a down-regulation of Mcl-2 and phosphorylated Bad proteins, which are anti-apoptotic factors and belong to the Bcl-2 family. On the other hand, expression levels of the other anti-apoptotic factors, such as FLICE-inhibitory protein (FLIP), Bcl-2 and Bcl-XL, which are associated with the Fas-mediated apoptotic signal pathway, did not change after LY294002 treatment. We concluded that: 1) the PI3K-Akt pathway plays an important role in preventing Fas-mediated apoptosis; and 2) a PI3 K inhibitor, such as LY294002, might be a useful anti-tumoral agent for gastric carcinoma.

Araki T, Hayashi M, Watanabe N, Kanuka H, Yoshino J, Miura M, Saruta T (2002) Down-regulation of Mcl-1 by inhibition of the PI3-K/Akt pathway is required for cell shrinkage-dependent cell death. Biochem Biophys Res Commun 290:1275–1281CrossRefPubMed

Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64:280–285PubMed

Brenner W, Farber G, Harget T, Lehr HA, Hengstler JG, Thuroff JW (2002) Loss of tumor suppressor protein PTEN during renal carcinogenesis. Int J Cancer 99:53–57CrossRefPubMed

Burger MM, Harris C (1995) UICC study group on basic and clinical cancer research: apoptosis in normal and tumour cells. Int J Cancer 60:590–592PubMed

Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3- kinase /Akt pathway. Proc Natl Acad Sci 96:4240–4245CrossRefPubMed

Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM, Vogt PK (1997) Transformation of chicken cells by the gene encoding the catalytic subunit of PI3-kinase. Science 276:1848–1850PubMed

Cheng J, Godwin A, Bellacosa A, Taguchi T, Franke T, Hamilton T, Tsichlis P, Testa J (1992) AKT2, a putative oncogene encoding a number of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci USA 89:9267–9271PubMed

Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR (1996) Amplification of AKT2 is human pancreatic cancer cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 93:3636–3641PubMed

Conover CA, Bale LK, Durham SK, Powell DR (2000) Insulin- like growth factor (IGF) binding protein-3 potentiation of IGF action is mediated through the phosphatidylinositol-3-kinase pathway and is associated with alteration in protein kinase B/AKT sensitivity. Endocrinology 141:3098–3103PubMed

Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Gene Dev 13:2905–2927CrossRef

Downward J (1999) How Bad phosphorylation is good for survival. Nat Cell Biol 1:E33-E35PubMed

Franke TF, Kaplan DR, Cantley LC (1997) PI3 K: downstream AKTion blocks apoptosis. Cell 88:435–437PubMed

Hayashi H, Tatebe S, Osaki M, Goto A, Suzuki Y, Ito, H (1997) Expression of Fas antigen and its mediation of apoptosis in human gastric cancer cell lines. Jpn J Cancer Res 88:49–55PubMed

Hengst L, Reed SI (1996) Translational control of p27/Kip1 accumulation during the cell cycle. Science 271:1861–1864PubMed

Hockenbery D (1995) Defining apoptosis. Am J Pathol 146:16–19

Houghton J A, Harwood FG, Gibson AA, Tillman DM (1997) The fas signaling pathway is functional in colon carcinoma cells and induces apoptosis. Clin Cancer Res 3:2205–2209PubMed

Hu S, Vincentz, C, Ni J, Genyz R, Dixit VM (1997) I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1 –and CD-95-induced apoptosis. J Biol Chem 272:17255–17257CrossRefPubMed

Huang HM, Huang CJ, Yen JJ (2000) Mcl-1 is a common target of stem cell factor and interleukin-5 for apoptosis prevention activity via MEK/MAPK and PI-3 K/Akt pathways. Blood 96:1764–1771PubMed

Irmler M, Thome M, Harne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190- 195PubMed

Kandasamy K, Srivastava RK (2002) Role of the phosphatidylinositol 3’-kinase/PTEN/Akt kinase pathway in tumor necrosis-related apoptosis- inducing ligand-induced apoptosis in non-small cell lung cancer cells. Cancer Res 62:4929–4937PubMed

Kang YH, Lee HS, Kim WH (2002) Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest 82:285–291PubMed

Khwaja A (1999) Akt is more than just a Bad kinase. Nature 401:33–34CrossRefPubMed

Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter, ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)- associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579–5588PubMed

Lee SH, Shin MS, Kim HS, Park WS, Kim SY, Jang JJ, Rhim KJ, Jang J, Lee HK, Park JY, Oh RR, Han SY, Lee JH, Lee JY, Yoo NJ (1999) Somatic mutation of Fas (Apo-1/CD95) gene in cutaneous squamous cell carcinoma arising from a burn scar. J Invest Dermatol 114:122–126CrossRef

Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501PubMed

Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490PubMed

MacKeigan JP, Taxman DJ, Hunter D, Earp III HS, Graves LM, Ting JP- Y (2002) Inactivation of the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway by the combined treatment of taxol and mitogen-activated protein kinase inhibition. Clin Cancer Res 8:2091–2099PubMed

Nagata S (1997) Apoptosis by death factor. Cell 88:355–365PubMed

O’Gorman DM, McKenna SL, McGahon AJ, Cotter TG (2001) Inhibition of PI3-kinase sensitises HL60 human leukemia cells to both chemotherapeutic drug- and Fas-induced apoptosis by a JNK independent pathway. Leukemia Res 25:801–811CrossRef

Osaki M, Kase S, Kodani I, Watanabe M, Adachi H, Ito H (2001) Expression of Fas and Fas ligand in human gastric adenomas and intestinal-type carcinomas: correlation with proliferation and apoptosis. Gastric Cancer 4:198–205CrossRefPubMed

Pagano M, Tam SW, Theodoras AM, Beer-Romero P, DelSal G, Chau V, Yew PR, Draetta GF, Rolfe M (1995) Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269:682–685PubMed

Panka DJ, Mana T, Suhara T, Walsh K, Mier JW (2001) Phosphatidylinositol 3-kinase/Akt activety regulates c-FLIP expression in tumor cells. J Biol Chem 276:6893–6896CrossRefPubMed

Park SW, Oh RR, Kim YS, Park JY, Lee SH, Shin MS, Kim SY, Kim PJ, Lee HK, Yoo NJ, Lee JY (2001) Somatic mutations in the death domain of the Fas (Apo-1/CD95) gene in gastric cancer. J Pathol 193:162–168CrossRefPubMed

Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE (2000) Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 275:10761–10766CrossRefPubMed

Rasper DM, Vaillancourt JP, Hadano S, Houtzager VM, Seiden I, Keen SL, Tawa P, Xanthoudakis S, Nasir J, Martindate D, Koop BF, Peterson EP, Thronberry NA, Huang J, MacPherson DP, Black SC, Hornung F, Lenardo MJ, Hayden MR, Roy S, Nicholson DW (1998) Cell death attenuation by ‘Usurpin’, a mammalian DED-caspase homologue that precludes caspase- 8 recruitment and activation by the CD-95 (Fas, Apo-1) receptor complex. Cell Death Differ 5:271–288PubMed

Semba S, Itoh N, Ito M, Harada M, Yamakawa M (2002) The in vitro and in vivo effects of 2-(4-morpholinyl)-8-phenyl-chrome (LY294002), a specific inhibitor of phosphatidylinositol 3’-kinase, in human colon cancer cells. Clin Cancer Res 8:1957–1963PubMed

Siegel RM, Chan FK, Chun HJ, Lenardo MJ (2000) The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. Nat Immunol 1:469–474CrossRefPubMed

Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, Liu DD, Kurie JM, Mao L, Khuri FR (2002) Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 8:1178–1184PubMed

Stambolic V, Mak TW, Woodgett JR (1999) Modulation of cellular apoptotic potential: contributions of oncogenesis. Oncogene 18:6094- 6103CrossRefPubMed

Stewart BW (1994) Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators. J Natl Cancer Inst 86:1286–1296PubMed

Takahashi R, Deveraux Q, Tamm I, Welsh K, Assa-Munt N, Salvesen GS, Reed JC (1998) A single BIR domain of XIAP sufficient for inhibiting caspases. J Biol Chem 273:7787–7790PubMed

Takayama H, Takakuwa T, Dong Z, Nonomura N, Okuyama A, Nagata S, Aozasa K (2001) Fas gene mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens. Lab Invest 81:283–288PubMed

Timmer T, de Vries EG, de Jong S (2002) Fas receptor-mediated apoptosis: a clinical application? J Pathol 196:125–134CrossRefPubMed

Ullich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212PubMed

Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346:561–576PubMed

Vassilev A, Ozer Z, Navara C, Mahajan S, Uckun FM (1999) Bruton’s tyrosine kinase as an inhibitor of the Fas/CD95 death-inducing signal complex. J Biol Chem 274:1646–1656CrossRefPubMed

Viglietto G, Motti ML, Buuni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M (2002) Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27^Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8:1136–1144CrossRefPubMed

Wallach D, Varfolomeey EE, Malinin NL, Goltsey YV, Kovalenko AV, Boldin MP (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17:331–367

Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF (1999) The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 19:6195–6206PubMed

Wang Y, Chan S, Tsang BK (2002) Involvement of inhibitory nuclear factor-kappaB (NfkappaB)-independent NfkappaB activation in the gonadotropic regulation of X-linked inhibitor of apoptosis expression during ovarian follicular development in vitro. Endocrinology 143:2732–2740CrossRefPubMed

Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S (1992) Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356:314–317PubMed

Yao Z, Okabayashi Y, Yotsudo Y, Kitamura T, Ogawa W, Kasuga M (2002) Role of Akt in growth and survival of PANC-1 pancreatic cancer cells. Pancreas 24:42–46CrossRefPubMed

Zhang XD, Franco AV, Myers K, Gray CP, Nguyen T, Hersey P (1999) Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res 59:2747–2753PubMed

Zhang XD, Franco AV, Nguyen T, Gray CP, Hersey P (2000) Differential localization and regulation of death and decoy receptors for TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells. J Immunol 164:3961–3970PubMed

Titel: Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45
verfasst von: Mitsuhiko Osaki
Satoru Kase
Keiko Adachi
Ami Takeda
Kiyoshi Hashimoto
Hisao Ito
Publikationsdatum: 01.01.2004
Verlag: Springer-Verlag
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 1/2004
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-003-0505-z

Springer Medizin

Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45

Abstract

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2004

Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells

Increased expression of MMP-2 and MMP-9 in esophageal squamous cell carcinoma.

Enhancement of effects of irradiation by gemcitabine in a glioblastoma cell line and cell line spheroids

Determination of vascular endothelial growth factor (VEGF) overexpression in soft tissue sarcomas and the role of overexpression in leiomyosarcoma

Initial experience with a novel desensitization strategy for carboplatin-associated hypersensitivity reactions: carboplatin-hypersensitivity reactions

The current and future role of dexrazoxane as a cardioprotectant in anthracycline treatment: expert panel review

Neu im Fachgebiet Onkologie

Adjuvante Immuntherapie verlängert Leben bei RCC

Alectinib verbessert krankheitsfreies Überleben bei ALK-positivem NSCLC

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Update Onkologie