Abstract
As tumors grow and invade beyond their homeostatic limits, the tumor cells are subjected to insufficient nutrient and oxygen supplies because of excessive demand for nutrition and oxygen, and insufficient vascularization. We therefore hypothesized that tolerance to nutrient deprivation as well as angiogenesis may be critical in some malignancies, including pancreatic cancers, which are seen to be a hypovascular tumor. In this study, we assessed the effect of AMP-activated protein kinase (AMPK), which plays a major role in protecting cells from metabolic stresses, on tumor biology under nutrient-deprived condition. Whereas hepatic cancer cells had mostly died within 48 h during glucose deprivation, most pancreatic cancer cells survived more than 48 h. The tolerance to glucose deprivation tended to correlate with the cells level of expression of AMPK α1 and α2. The introduction of AMPK antisense RNA expression vectors into pancreas cancer cell lines, PANC-1 and AsPC-1, significantly diminished their tolerance to glucose deprivation, and the stable transfection of AMPK antisense into PANC-1 cells inhibited tumor growth in nude mice. These findings indicate that AMPK expression contributes to tolerance to nutrient starvation in cancer cells. We propose AMPK as a new target for therapeutic strategies to suppress tumor growth and invasion.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- AS:
-
antisense
- AMPK:
-
AMP-activated protein kinase
- AICAR:
-
5-amino-4-imidazole carboxamide riboside
References
Aguan K, Scott J, See CG, Sarkar NH . 1994 Gene 149: 345–350
Barinaga M . 1997 Science 275: 482–484
Brown JM, Giaccia AJ . 1998 Cancer Res. 58: 1408–1416
Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E . 1998 Nature 394: 485–490
Carling D, Aguan K, Woods A, Verhoeven AJ, Beri RK, Brennan CH, Sidebottom C, Davison MD, Scott J . 1994 J. Biol. Chem. 269: 11442–11448
Chomczynski P, Sacchi N . 1987 Anal. Biochem. 162: 156–159
Crute BE, Seefeld K, Gamble J, Kemp BE, Witters LA . 1998 J. Biol. Chem. 273: 35347–35354
Corton JM, Gillespie JG, Hardie DG . 1994 Curr. Biol. 4: 315–324
Dang CV, Semenza GL . 1999 Trends Biochem. Sci. 24: 68–72
da Silva Xavier G, Leclerc I, Salt IP, Doiron B, Hardie DG, Kahn A, Rutter GA . 2000 Proc. Natl. Acad. Sci. USA 97: 4023–4028
Folkman J . 1995 Nat. Med. 1: 27–31
Foretz M, Carling D, Guichard C, Ferre P, Foufelle F . 1998 J. Biol. Chem. 273: 14767–14771
Hardie DG, Carling D . 1997 Eur. J. Biochem. 246: 259–273
Hashimoto K, Kato K, Imamura K, Kishimoto A, Yoshikawa H, Taketani Y, Esumi H . 2001 Biochem. Biophys. Res. Commun. 290: 263–267
Hayashi T, Hirshman MF, Kurth EJ, Winder WW, Goodyear LJ . 1998 Diabetes 47: 1369–1373
Helmlinger G, Yuan F, Dellian M, Jain R . 1997 Nat. Med. 3: 177–182
Hockel M, Schlenger K, Hockel S, Vaupel P . 1999 Cancer Res. 59: 4525–4528
Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ . 1999 Science 284: 1994–1998
Heyer BS, Warsowe J, Solter D, Knowles BB, Ackerman SL . 1997 Mol. Reprod. Dev. 47: 148–156
Izuishi K, Kato K, Ogura T, Kinoshita T, Esumi H . 2000 Cancer Res. 60: 6201–6207
Koito K, Namieno T, Nagakawa T, Morita K . 1997 Am. J. Roentgenol. 169: 1263–1267
Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD . 1995 J. Biol. Chem. 270: 17513–17520
Lefebvre DL, Bai Y, Shahmolky N, Poon R, Drucker DJ, Rosen CF . 2001 Biochem. J. 355: 297–305
Mitchelhill KI, Stapleton D, Gao G, House C, Michell B, Katsis F, Witters LA, Kemp BE . 1994 J. Biol. Chem. 269: 2361–2364
Pines J . 1995 Semin. Cancer Biol. 6: 63–72
Rofstad EK, Danielsen T . 1999 Br. J. Cancer 80: 1697–1707
Saaristo A, Karpanen T, Alitalo K . 2000 Oncogene 19: 6122–6129
Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE . 1996 J. Biol. Chem. 271: 611–614
Sutherland RM . 1988 Science 240: 177–184
Tomida A, Suzuki H, Kim H, Tsuruo T . 1996 Oncogene 13: 2699–2705
Wartenberg M, Dönmez F, Ling FC, Acker H, Hescheler J, Sauer H . 2001 FASEB J. 15: 995–1005
Woods A, Salt I, Scott J, Hardie DG, Carling D . 1996 FEBS Lett. 397: 347–351
Xia Y, Zhang Z, Kruse U, Vogt PK, Li J . 2000 Biochem. Biophys. Res. Commun. 276: 564–570
Acknowledgements
This work was supported in part by a Grant from Ministry of Health and Welfare for the 2nd-term 10-year Comprehensive Strategy for Cancer Control and Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare and Ministry of Education, Science, Sports, and Culture of Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kato, K., Ogura, T., Kishimoto, A. et al. Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene 21, 6082–6090 (2002). https://doi.org/10.1038/sj.onc.1205737
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205737
Keywords
This article is cited by
-
Proteomics-based target identification of natural products affecting cancer metabolism
The Journal of Antibiotics (2021)
-
AMPKα-like proteins as LKB1 downstream targets in cell physiology and cancer
Journal of Molecular Medicine (2021)
-
Collagen metabolism as a regulator of proline dehydrogenase/proline oxidase-dependent apoptosis/autophagy
Amino Acids (2021)
-
An integrative pan-cancer investigation reveals common genetic and transcriptional alterations of AMPK pathway genes as important predictors of clinical outcomes across major cancer types
BMC Cancer (2020)
-
Defining a metabolic landscape of tumours: genome meets metabolism
British Journal of Cancer (2020)