Abstract
Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumor malignancy. In the present study, we investigated the mechanism underlying hypoxia-modulated apoptosis of serum-deprived HepG2 cells. Our results showed that hypoxia blocked the apoptosis, which was accompanied with decreased Bax/Bcl-2 ratio, inhibited cytochrome c release, and reduced caspase-3 activity. More importantly, increased expressions of VEGF and its receptor-2 (KDR) under hypoxic/serum-deprived condition suggest that VEGF may act as a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum deprivation-induced apoptosis, and anti-VEGF neutralizing antibody block anti-apoptotic activity of hypoxia. In addition, inhibitors of receptor tyrosine kinase blocked anti-apoptosis of hypoxia. Our study further showed that rhVEGF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a specific inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic activity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 activity. Our data led us to conclude that induction of ERK phosphorylation and decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxia-induced VEGF prevents apoptosis of serum-deprived cells by activating the MAPK/ERK pathway. Taken together, we propose that hypoxia enhances survival of nutrient-depleted tumor cells by reducing susceptibility to apoptosis, which consequently leads to tumor malignancy.
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References
Alon T, Hemo I, Itin A, Pe’er J, Stone J and Keshet E. . 1995 Nat. Med. 1: 1024–1028.
Ausserer WA, Bourrat-Floeck B, Green CJ, Laderoute KR and Sutherland RM. . 1994 Mol. Cell Biol. 14: 5032–5042.
Bae SK, Baek JH, Lee YM, Lee OH and Kim KW. . 1998 Cancer Lett. 126: 97–104.
Baek JH, Lee YS, Kang CM, Kim JA, Kwon KS, Son HC and Kim KW. . 1997 Int. J. Cancer 73: 725–728.
Baek JH, Kang CM, Chung HY, Park MH and Kim KW. . 1996 J. Biochem. Mol. Biol. 29: 68–72.
Bhalla RC, Toth KF, Bhatty RA, Thompson LP and Sharma RV. . 1997 Am. J. Physiol. 272: H1996–H2003.
Boix J, Fibla J, Yuste V, Piulats JM, Llecha N and Comella JX. . 1998 Exp. Cell Res. 238: 422–429.
Chinnaiyan AM and Dixit VM. . 1996 Curr. Biol. 6: 555–562.
Dang CV and Semenza GL. . 1999 TIBS 24: 68–72.
Dhanabal M, Ramchandran R, Waterman MJ, Lu H, Knebelmann B, Segal M and Sukhatme VP. . 1999 J. Biol. Chem. 274: 11721–11726.
Dolbeare F and Selden JR. . 1994 Methods Cell Biol. 41: 297–316.
Dvorak HF, Sioussat TM, Brown LF, Berse B, Nagy JA, Sotrel A, Manseau EJ, Van de Water L and Senger DR. . 1991 J. Exp. Med. 174: 1275–1278.
Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG and Green DR. . 1999 J. Biol. Chem. 274: 2225–2233.
Gotz ME, Ahlbom E, Zhivotovsky B, Blum-Degen D, Oettel M, Romer W, Riederer P, Orrenius S and Ceccatelli S. . 1999 J. Neurosci. Res. 56: 420–426.
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW and Giaccia AJ. . 1996 Nature 379: 88–91.
Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY and Hebbel RP. . 1999 Exp. Cell Res. 247: 495–504.
Harrington EA, Fanidi A and Evan GI. . 1994 Curr. Opin. Genet. Dev. 4: 120–129.
Henkart PA. . 1996 Immunity 4: 195–201.
Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U and Vaupel P. . 1996 Cancer Res. 56: 4509–4515.
Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD and Wiegand SJ. . 1999 Science 284: 1994–1998.
Jinno H, Steiner MG, Mehta RG, Osborne MP and Telang NT. . 1999 Carcinogenesis 20: 229–236.
Kim KW, Bae SK, Lee OH, Bae MH, Lee MJ and Park BC. . 1998 Cancer Res. 58: 348–351.
Kluck RM, Bossy-Wetzel E, Green DR and Newmeyer DD. . 1997 Science 275: 1132–1136.
Kroemer G, Dallaporta B and Resche-Rigon M. . 1998 Annu. Rev. Physiol. 60: 619–642.
Kroll J and Waltenberger J. . 1997 J. Biol. Chem. 272: 32521–32527.
Kwo P, Patel T, Bronk SF and Gores GJ. . 1995 Am. J. Physiol. 268: G613–621.
Levy AP, Levy NS, Wegner S and Goldberg MA. . 1995 J. Biol. Chem. 270: 13333–13340.
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X. . 1997 Cell 91: 479–489.
Liu X, Kim CN, Yang J, Jemmerson R and Wang X. . 1996 Cell 86: 147–157.
Marzo I, Brenner C, Zamzami N, Jurgensmeier JM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC and Kroemer G. . 1998 Science 281: 2027–2031.
Mukhopadhyay D, Nagy JA, Manseau EJ and Dvorak HF. . 1998 Cancer Res. 58: 1278–1284.
Nomura M, Yamagishi S, Harada S, Hayashi Y, Yamashima T, Yamashita J and Yamamoto H. . 1995 J. Biol. Chem. 270: 28316–28324.
Piossek C, Schneider-Mergener J, Schirner M, Vakalopoulou E, Germeroth L and Thierauch KH. . 1999 J. Biol. Chem. 274: 5612–5619.
Rempel A, Mathupala SP, Griffin CA, Hawkins AL and Pedersen PL. . 1996 Cancer Res. 56: 2468–2471.
Roy N, Deveraux QL, Takahashi R, Salvesen GS and Reed JC. . 1997 EMBO J. 16: 6914–6925.
Rupec RA and Baeuerle PA. . 1995 Eur. J. Biochem. 234: 632–640.
Satoh T, Sakai N, Enokido Y, Uchiyama Y and Hatanaka H. . 1996 Brain Res. 733: 9–14.
Schuster SJ, Badiavas EV, Costa-Giomi P, Weinmann R, Erslev AJ and Caro J. . 1989 Blood 73: 13–16.
Semenza GL, Roth PH, Fang HM and Wang GL. . 1994 J. Biol. Chem. 269: 23757–23763.
Sentman CL, Shutter JR, Hockenbery D, Kanagawa O and Korsmeyer SJ. . 1991 Cell 67: 879–888.
Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T and Van Dyke T. . 1994 Cell 78: 703–711.
Takahashi N, Seko Y, Noiri E, Tobe K, Kadowaki T, Sabe H and Yazaki Y. . 1999 Circ. Res. 84: 1194–1202.
Towle HC. . 1995 J. Biol. Chem. 270: 23235–23238.
van Engeland M, Nieland LJ, Ramaekers FC, Schutte B and Reutelingsperger CP. . 1998 Cytometry 31: 1–9.
Wang TT and Phang JM. . 1995 Cancer Res. 55: 2487–2489.
Wyllie AH, Kerr JF and Currie AR. . 1980 Int. Rev. Cytol. 68: 251–306.
Wyllie AH. . 1995 Curr. Opin. Genet. Dev. 5: 97–104.
Younes M, Lechago LV, Somoano JR, Mosharaf M and Lechago J. . 1996 Cancer Res. 56: 1164–1167.
Acknowledgements
We thank Drs Byung Pal Yu, You-Mie Lee, Hee Young Cho (Pusan National University, Korea), Yong Soo Lee (Kwangdong University, Korea) and Jung-Ae Kim (Yeungnam University, Korea) for critical comments on the manuscript. This work was supported by the National Research Laboratory Fund, the Ministry of Science and Technology, Korea.
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Baek, J., Jang, JE., Kang, CM. et al. Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene 19, 4621–4631 (2000). https://doi.org/10.1038/sj.onc.1203814
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DOI: https://doi.org/10.1038/sj.onc.1203814
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