Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation

Oncogene volume 22, pages 6177–6182 (2003)Cite this article

Abstract

AMPK is a serine/threonine protein kinase family and we recently identified a novel member, ARK5. The activation of ARK5 is triggered by Akt, and ARK5 induces tumor cell survival during nutrient starvation. In the current study, we investigated the mechanisms of induction of cell survival by ARK5. Human hepatoma HepG2 cells undergo necrotic cell death within 24 h after the start of glucose starvation, and the cell death signaling has been found to be mediated by death-receptor-independent activation of caspase 8. When HepG2 cells were transfected with ARK5 expression vector and subjected to several cell death stimuli, ARK5 was found to suppress cell death by glucose starvation, TRAIL, and TNF-α, but not by ultraviolet irradiation, camptothecin, or doxorubicin. Western blotting analysis revealed that both TRAIL and glucose starvation induced Bid cleavage and FLIP degradation following caspase 8 activation in a time-dependent manner, and ARK5 overexpression clearly delayed Bid cleavage, FLIP degradation, and caspase 8 activation. On the basis of the results of this study, we report that cell survival induced by ARK5 is, at least in part, due to inhibition of caspase 8 activation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

Abbreviations

AMPK:

AMP-activated protein kinase

CPT:

camptothecin

Dox:

doxorubicin

PI:

propidium iodide

TNF:

tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

UV:

ultraviolet

References

  • Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornbery NA, Wong WW and Yuan J . (1996). Cell, 87, 171.

  • Boldin MP, Goncharov TM, Golstev YV and Wallach D . (1996). Cell, 85, 803–815.

  • Brazil DP, Park J and Hemmings BA . (2002). Cell, 111, 293–303.

  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S and Reed JC . (1998). Science, 282, 1318–1321.

  • Chinnaiyan AM, O'Rourke K, Tewari M and Dixit VM . (1995). Cell, 81, 505–512.

  • Datta SR, Brunet A and Greenberg ME . (1999). Genes Dev., 13, 2905–2927.

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME . (1997). Cell, 91, 231–241.

  • Delcommenne M, Tan C, Gray V, Rue L, Woodgett J and Dedhar S . (1998). Proc. Natl. Acad. Sci. USA, 95, 11211–11216.

  • Esumi H, Izuishi K, Kato K, Hashimoto K, Kurashima Y, Kishimoto A, Ogura T and Ozawa T . (2002). J. Biol. Chem., 277, 32791–32798.

  • Folkman J . (1974). Adv. Cancer Res., 19, 331–358.

  • Folkman J . (2001). Proc. Natl. Acad. Sci. USA, 98, 398–400.

  • Green DR and Reed JC . (1998). Science, 281, 1309–1312.

  • Gupta S . (2001). Curr. Mol. Med., 1, 317–324.

  • Hasegawa J, Kamada S, Kamiike W, Shimizu S, Imazu T, Matsuda H and Tsujimoto Y . (1996). Cancer Res., 56, 1713–1718.

  • Hashimoto K, Kato K, Imamura K, Kishimoto A, Yoshikawa H, Taketani Y and Esumi H . (2002). Biochem. Biophys. Res. Commun., 290, 263–267.

  • Heyer BS, Warsowe J, Solter D, Knowles BB and Ackerman SL . (1997). Mol. Reprod. Dev., 47, 148–156.

  • Higuchi M, Masuyama N, Fukui Y, Suzuki A and Gotoh Y . (2001). Curr. Biol., 11, 1958–1962.

  • Irmler M, Thome M, Hahne M, Schneider P, Hofman K, Steiner V, Bodmer J-L, Schroter M, Burns K, Mattman C, Rimoldi D, French LE and Tschopp J . (1997). Nature, 388, 190–195.

  • Izuishi K, Kato K, Ogura T, Kinoshita T and Esumi H . (2000). Cancer Res., 60, 6201–6207.

  • Kato K, Ogura T, Kishimoto A, Minegishi Y, Nakajima N, Miyazaki M and Esumi H . (2002). Oncogene, 21, 6082–6090.

  • Kaufmann SH . (1998). Biochem. Biophys. Acta, 1400, 195–211.

  • Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN and Hay N . (1997). Genes Dev., 11, 701–713.

  • Kim Y, Suh N, Sporn M and Reed JC . (2002). J. Biol. Chem., 277, 22320–22329.

  • Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH and Peter ME . (1995). EMBO J., 14, 5579–5588.

  • Kulms D and Schwarz T . (2002). J. Dermatol., 29, 189–196.

  • Lage H and Dietel M . (1999). J. Cancer Res. Clin. Oncol., 125, 156–165.

  • Lefebvre DL, Bai Y, Shahmolky N, Poon R, Drucker DJ and Rosen CF . (2001). Biochem. J., 355, 297–305.

  • Li H, Zhu H, Xu CJ and Yuan J . (1998). Cell, 94, 491–501.

  • Luo X, Budihardjo I, Zou H, Slaughter C and Wang X . (1998). Cell, 94, 481–490.

  • Mitchelhill KI, Stapleton D, Gao G, House C, Michell B, Katsis F, Witters LA and KB E . (1994). J. Biol. Chem., 269, 2361–2364.

  • Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME and Dixit VM . (1996). Cell, 85, 817–827.

  • Nagata S . (1997). Cell, 88, 355–365.

  • Nam SY, Amoscato AA and Lee YJ . (2002). Oncogene, 21, 337–346.

  • Pan G, Ni J, Wei YF, Yu G, Gentz R and Dixit VM . (1997). Science, 277, 815–818.

  • Scaffidi C, Schmitz I, Krammer PH and Peter ME . (1999). J. Biol. Chem., 274, 1541–1548.

  • Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Remakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P and Ashkenazi A . (1997). Science, 277, 818–821.

  • Shimizu S, Eguchi Y, Kamiike W, Waguri S, Uchiyama Y, Matsuda H and Tsujimoto Y . (1996). Oncogene, 12, 2045–2050.

  • Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA and Kemp BE . (1996). J. Biol. Chem., 611–614.

  • Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM and Cheresh DA . (2001). J. Cell Biol., 155, 459–470.

  • Suzuki A, Kusakai G, Kishimoto A, Lu J, Ogura T, Lavin MF and Esumi H . (2003). J. Biol. Chem., 278, 48–53.

  • Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schroter M, Scaffidi C, Krammer PH, Peter ME and Tschopp J . (1997). Nature, 386, 517–521.

  • Tsujimoto Y, Yunis J, Nowell PC and Croce CM . (1984). Science, 226, 1097–1099.

  • Vaux DL, Cory S and Adams JM . (1988). Nature, 335, 440–442.

  • Wang K, Yin XM, Chao DT, Milliman CL and Korsmeyer SJ . (1996). Genes Dev., 10, 2859–2869.

  • Yamanaka T, Shiraki K, Sugimoto K, Ito T, Fujikawa K, Ito M, Takase K, Moriyama M, Nakano T and Suzuki A . (2000). Hepatology, 32, 482–490.

Download references

Acknowledgements

This work was partly supported by a grant for the second-term comprehensive 10-year strategy of cancer control from the Ministry of Health, Welfare and Labour, and a grant for Medical Frontier Program from the Ministry of Health, Welfare and Labour. AS, GK, and JL are recipients of the Research Resident Fellowship Award from the Foundation for Promotion of Cancer Research.

Author information

Authors and Affiliations

  1. Investigative Treatment Division, National Cancer Center Research Institute East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Atsushi Suzuki, Gen-ichi Kusakai, Atsuhiro Kishimoto, Jie Lu, Tsutomu Ogura & Hiroyasu Esumi

Authors
  1. Atsushi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gen-ichi Kusakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsuhiro Kishimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jie Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsutomu Ogura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroyasu Esumi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroyasu Esumi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Suzuki, A., Kusakai, Gi., Kishimoto, A. et al. ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation. Oncogene 22, 6177–6182 (2003). https://doi.org/10.1038/sj.onc.1206899

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206899

Keywords

This article is cited by

Search

Advanced search

Quick links