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:

Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency

Oncogene volume 22, pages 4062–4073 (2003)Cite this article

Abstract

Two hepatocarcinoma cell lines, the Hepa-1 wild-type (c1c7) and the β-subunit mutated (c4) lacking hypoxia-inducible factor-1 (HIF-1) activity, were differentially susceptible to apoptosis by hepatocyte growth factor (HGF). The c4 cells were 40% apoptotic 48 h after HGF treatment. On the contrary, the wild-type c1c7 cells showed modest signs of apoptosis only at 72 h. The revertant vT{2} cells, consisting of c4 cells stably transfected with HIF-1β expression vector, behaved as the parental cells. To understand the mechanisms of this different sensitivity, we examined a panel of genes involved in apoptosis: ornithine decarboxylase, c-Myc and p53 protein levels progressively decreased while JNK1, caspase 8 and 3 activities persistently increased in c4 cells undergoing apoptosis. Distinct time-related events in c1c7 cells were the transient activations of JNK1 and caspase 8 followed by the accumulation of ODC and c-Myc proteins. The proapoptotic effect of HGF in c4 hepatocarcinoma cells seems to be related to HIF-1 deficiency with loss of cytoprotective and signalling functions. This may contribute to the triggering of the extrinsic pathway consisting in caspase 8 activation, which in turn causes BID cleavage and cytochrome c release. The effector caspase 3 is also activated.

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
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR, Davis RJ and Ronai Z-e . (1999). EMBO J., 18, 1321–1334.

  • Adrain C and Martin SJ . (2001). Trends Biochem. Sci., 26, 390–397.

  • Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, Niizeki H, Kawamura K-i, Hosokawa M and Asaka M . (2001). Cancer Res., 61, 6548–6554.

  • Alfranca A, Gutiérrez MD, Vara A, Aragonés J, Vidal F and Landázuri MO . (2002). Mol. Cell. Biol., 22, 12–22.

  • Arakaki N, Kajihara T, Arakaki R, Ohnishi T, Kazi JA, Nakashima H and Daikuhara Y . (1999). J. Biol. Chem., 274, 13541–13546.

  • Baek JH, Jang JE, Kang CM, Chung HY, Kim ND and Kim KW . (2000). Oncogene, 19, 4621–4631.

  • Bendinelli P, Piccoletti R, Maroni P and Bernelli-Zazzera A . (1996). FEBS Lett., 398, 193–197.

  • Bowers DC, Fan S, Walter K, Abounder R, Williams JA, Rosen EM and Laterra J . (2000). Cancer Res., 60, 4277–4283.

  • Chen C-Y, Juo P, Liou JS, Li C-Q, Yu Q, Bleins J and Faller DV . (2001). Cell Growth Differ., 12, 297–306.

  • Conner EA, Wirth PJ, Kiss A, Santoni-Rugiu E and Thorgeirsson SS . (1997). Biochem. Biophys. Res. Commun., 236, 396–401.

  • Desiderio MA, Grassilli E, Bellesia E, Salomoni P and Franceschi C . (1995). Cell Growth Differ., 6, 505–513.

  • Dragovich T, Rudin CM and Thompson CB . (1998). Oncogene, 17, 3207–3213.

  • Fan S, Ma YX, Gao M, Yuan R-Q, Meng Q, Goldberg ID and Rosen EM . (2001). Mol. Cell. Biol., 21, 4968–4984.

  • Fan S, Ma YX, Wang J-A, Yuan R-Q, Meng Q, Cao Y, Laterra J, Goldberg ID and Rosen EM . (2000). Oncogene, 19, 2212–2223.

  • Fan S, Wang J-A, Yuan R-Q, Rockwell S, Andres J, Zlatapolskiy A, Goldberg ID and Rosen EM . (1998). Oncogene, 17, 131–141.

  • Grassilli E, Benatti F, Dansi P, Giammarioli AM, Malorni W, Franceschi C and Desiderio MA . (1998). Biochem. Biophys. Res. Commun., 250, 293–297.

  • Gross A, Yin X-M, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P and Korsmeyer SJ . (1999). J. Biol. Chem., 274, 1156–1163.

  • Hoffman EC, Reyes H, Chu F-F, Sander F, Conley LH, Brooks BA and Hankinson O . (1991). Science, 252, 954–958.

  • Jesenberg V and Jentsch S . (2002). Nat. Rev. Mol. Cell. Biol., 3, 112–121.

  • Katoh O, Takahashi T, Oguri T, Kuramoto K, Mihara K, Kobayashi M, Hirata S and Watanabe H . (1998). Cancer Res., 58, 5565–5569.

  • Lundberg AS and Weinberg RA . (1999). Eur. J. Cancer, 35, 1886–1894.

  • Maggiora P, Gambarotta G, Olivero M, Giordano S, Di Renzo MF and Comoglio PM . (1997). J. Cell. Physiol., 173, 183–186.

  • Mar PK, Kumar AP, Kang D-C, Zhao B, Martinez LA, Montgomery RL, Anderson L and Butler AP . (1995). Mol. Carcinog., 14, 240–250.

  • Matteucci E, Castoldi R and Desiderio MA . (2001). J. Cell. Physiol., 186, 387–396.

  • Minet E, Michel G, Mottet D, Raes M and Michiels C . (2001). Free Radical Biol. Med., 31, 847–855.

  • Murakami Y, Matsufuji S, Hayashi S-i, Tanahashi N and Tanaka K . (2000). Biochem. Biophys. Res. Commun., 267, 1–6.

  • Noguchi K, Kokubu A, Kitanaka C, Ichijo H and Kuchino Y . (2001). Biochem. Biophys. Res. Commun., 281, 1313–1320.

  • Orlowski RZ . (1999). Cell Death Differ., 6, 303–313.

  • Richard DE, Berra E, Gothi é E, Roux D and Pouysségur J . (1999). J. Biol. Chem., 274, 32631–32637.

  • Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E and Birchmeier C . (1995). Nature, 373, 699–702.

  • Schmidt T, Korner K, Karsunky H, Korsmeyer S, Muller R and Moroy T . (1999). Cell Death Differ., 6, 873–882.

  • Schuler M and Green DR . (2001). Biochem. Soc. Transact., 29, 684–688.

  • Semenza GL . (2000). Genes Dev., 14, 1983–1991.

  • Soucie EL, Annis MG, Sedivy J, Filmus J, Leber B, Andrews DW and Penn LZ . (2001). Mol. Cell. Biol., 21, 4725–4736.

  • Suzuki H, Tomida A and Tsuruo T . (2001). Oncogene, 20, 5779–5788.

  • Tacchini L, Dansi P, Matteucci E and Desiderio MA . (2000). Exp. Cell Res., 256, 272–281.

  • Tacchini L, Dansi P, Matteucci E and Desiderio MA . (2001). Carcinogenesis, 22, 1363–1371.

  • Thomas T and Thomas TJ . (2001). Cell. Mol. Life Sci., 58, 244–258.

  • Trusolino M and Comoglio PM . (2002). Nat. Rev. Cancer, 2, 289–300.

  • Wang X, DeFrances MC, Dai Y, Pediaditakis P, Johnson C, Bell A, Michalopoulos K and Zarnegar R . (2002). Mol. Cell, 9, 411–421.

  • Williams KJ, Telfer BA, Airley RE, Peters HPW, Sheridan MR, van der Kogel AJ, Harris AL and Stratford IJ . (2002). Oncogene, 21, 282–290.

  • Wood SM, Gleadle JM, Pugh CW, Hankinson O and Ratcliffe PJ . (1996). J. Biol. Chem., 271, 15117–15123.

  • Woods DB and Vousden KH . (2001). Exp. Cell. Res., 264, 56–66.

  • Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF and Testa JR . (2001). Proc. Natl. Acad. Sci. USA, 98, 247–252.

  • Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T-I, Jones DP and Wang X . (1997). Science, 275, 1129–1132.

  • Zarnegar R and Michalopoulos GK . (1995). J. Cell Biol., 129, 1177–1180.

Download references

Acknowledgements

This work was supported by grants from the Consiglio Nazionale delle Ricerche (C.N.R.), Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.) and Ministero dell'Università e della Ricerca Scientifica e Tecnologica – Italy. We thank Dr O Hankinson, who kindly provided wild-type, mutated and stably transfected Hepa-1 cells.

Author information

Authors and Affiliations

  1. Institute of General Pathology, School of Medicine, University of Milano, via L. Mangiagalli, Milano, 31-20133, Italy

    Emanuela Matteucci, Silvia Modora & Maria Alfonsina Desiderio

  2. Department of Oncology, Flow Cytometry Unit, Istituto di Ricerche Farmacologiche Mario Negri, via Eritrea, Milano, 62-20157, Italy

    Matteo Simone

Authors
  1. Emanuela Matteucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia Modora
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matteo Simone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Alfonsina Desiderio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Alfonsina Desiderio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matteucci, E., Modora, S., Simone, M. et al. Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency. Oncogene 22, 4062–4073 (2003). https://doi.org/10.1038/sj.onc.1206519

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206519

Keywords

This article is cited by

Search

Advanced search

Quick links