The gene expression alterations in chronic hypoxic PANC-1 pancreatic cancer cell line
Main Article Content
Keywords
Cancer, Cell Line, Gene Expression, Hyoxia, PANC-1
Abstract
Aim: Cancer cells divide excessively, resulting in overpopulation and hypoxia. Tumor hypoxia drives tumor development and therapeutic resistance. Hypoxia dominates pancreatic tumor microenvironments. This study aimed to ascertain alterations in gene expression linked to chronic hypoxia in the pancreatic cancer cell (PANC-1) line. Methods: PANC-1 had eight-hour hypoxic events with oxygen levels below 1%. 40 episodes were exposed three times a week. Real-time PCR arrays were used to analyze gene expression changes. This investigation compared cells treated with 20 and 40 hypoxia episodes to normoxic cells. MTT cell proliferation assays assessed hypoxic cell doxorubicin resistance. Wound-healing assays measured cell migration. 20 and 40 hypoxia exposures altered gene expression patterns significantly. Results: No alterations were observed in either stage, as most genes exhibited a resurgence after 40 episodes. Following exposure to 20 episodes of hypoxia, the expression levels of the genes HIF1AN, HMOX-1, and PKM were significantly increased by factors of 6.9, 4.5, and 3.4, respectively. The IC50 value of Doxorubicin in PANC-1 cells exhibited a 2.7-fold increase and an approximately 3.6-fold increase after 20 and 40 episodes, respectively, compared to normoxic cells. This study demonstrates that subjecting cells to extended durations of hypoxia results in distinct alterations in gene expression compared to those induced by short-term hypoxia, specifically lasting less than 72 hours. Furthermore, it sanctioned the facilitation of chemotherapy resistance through prolonged exposure. Conclusions: The study suggests that HIF1AN, HMOX-1, and PKM may serve as promising biomarkers for hypoxia in pancreatic cancer and contributors to the cellular response to prolonged hypoxia.
References
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2. Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin. Sep-Oct 2012;62(5):283-98. doi:10.3322/caac.21153
3. Lowenfels AB, Maisonneuve P. Risk factors for pancreatic cancer. J Cell Biochem. Jul 1 2005;95(4):649-56. doi:10.1002/jcb.20461
4. Registry JC. Cancer Incidence in Jordan Report. 2012;
5. Shaib YH, Davila JA, El-Serag HB. The epidemiology of pancreatic cancer in the United States: changes below the surface. Aliment Pharmacol Ther. Jul 1 2006;24(1):87-94. doi:10.1111/j.1365-2036.2006.02961.x
6. Burris HA, 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. Jun 1997;15(6):2403-13. doi:10.1200/jco.1997.15.6.2403
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8. Hazard L. The role of radiation therapy in pancreas cancer. Gastrointest Cancer Res. Jan 2009;3(1):20-8.
9. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol. 2001;18(4):243-59. doi:10.1385/mo:18:4:243
10. Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist. 2004;9 Suppl 5:4-9. doi:10.1634/theoncologist.9-90005-4
11. Yuan J, Glazer PM. Mutagenesis induced by the tumor microenvironment. Mutat Res. May 25 1998;400(1-2):439-46. doi:10.1016/s0027-5107(98)00042-6
12. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. Jan 2002;2(1):38-47. doi:10.1038/nrc704
13. Rofstad EK. Microenvironment-induced cancer metastasis. Int J Radiat Biol. May 2000;76(5):589-605. doi:10.1080/095530000138259
14. Subarsky P, Hill RP. The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis. 2003;20(3):237-50. doi:10.1023/a:1022939318102
15. Alqawi O, Wang HP, Espiritu M, Singh G. Chronic hypoxia promotes an aggressive phenotype in rat prostate cancer cells. Free Radic Res. Jul 2007;41(7):788-97. doi:10.1080/10715760701361531
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17. Hamdan FH, Zihlif MA. Gene expression alterations in chronic hypoxic MCF7 breast cancer cell line. Genomics. Dec 2014;104(6 Pt B):477-81. doi:10.1016/j.ygeno.2014.10.010
18. Greco O, Marples B, Joiner MC, Scott SD. How to overcome (and exploit) tumor hypoxia for targeted gene therapy. J Cell Physiol. Dec 2003;197(3):312-25. doi:10.1002/jcp.10374
19. Wardman P. Electron transfer and oxidative stress as key factors in the design of drugs selectively active in hypoxia. Curr Med Chem. Jun 2001;8(7):739-61. doi:10.2174/0929867013372959
20. Wouters A, Pauwels B, Lardon F, Vermorken JB. Review: implications of in vitro research on the effect of radiotherapy and chemotherapy under hypoxic conditions. Oncologist. Jun 2007;12(6):690-712. doi:10.1634/theoncologist.12-6-690
21. Lane DP. Cancer. p53, guardian of the genome. Nature. Jul 2 1992;358(6381):15-6. doi:10.1038/358015a0
22. Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer. Apr 2011;2(4):466-74. doi:10.1177/1947601911408889
23. Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer. Dec 2006;6(12):909-23. doi:10.1038/nrc2012
24. Hammond EM, Giaccia AJ. The role of p53 in hypoxia-induced apoptosis. Biochem Biophys Res Commun. Jun 10 2005;331(3):718-25. doi:10.1016/j.bbrc.2005.03.154
25. Banasiak KJ, Haddad GG. Hypoxia-induced apoptosis: effect of hypoxic severity and role of p53 in neuronal cell death. Brain Res. Jun 29 1998;797(2):295-304. doi:10.1016/s0006-8993(98)00286-8
26. Acin S, Li Z, Mejia O, Roop DR, El-Naggar AK, Caulin C. Gain-of-function mutant p53 but not p53 deletion promotes head and neck cancer progression in response to oncogenic K-ras. J Pathol. Dec 2011;225(4):479-89. doi:10.1002/path.2971
27. Fiorini C, Cordani M, Padroni C, Blandino G, Di Agostino S, Donadelli M. Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. Biochim Biophys Acta. Jan 2015;1853(1):89-100. doi:10.1016/j.bbamcr.2014.10.003
28. Zhu XF, Li W, Ma JY, et al. Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells. Oncol Lett. Nov 2015;10(5):2974-2980. doi:10.3892/ol.2015.3735
29. Shin YK, Yoo BC, Hong YS, et al. Upregulation of glycolytic enzymes in proteins secreted from human colon cancer cells with 5-fluorouracil resistance. Electrophoresis. Jun 2009;30(12):2182-92. doi:10.1002/elps.200800806
30. Guo W, Zhang Y, Chen T, et al. Efficacy of RNAi targeting of pyruvate kinase M2 combined with cisplatin in a lung cancer model. J Cancer Res Clin Oncol. Jan 2011;137(1):65-72. doi:10.1007/s00432-010-0860-5
31. Azoitei N, Becher A, Steinestel K, et al. PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation. Mol Cancer. Jan 6 2016;15:3. doi:10.1186/s12943-015-0490-2
32. Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V. Hexokinase-I protection against apoptotic cell death is mediated via interaction with the voltage-dependent anion channel-1: mapping the site of binding. J Biol Chem. May 9 2008;283(19):13482-90. doi:10.1074/jbc.M708216200
33. Brahimi-Horn MC, Ben-Hail D, Ilie M, et al. Expression of a truncated active form of VDAC1 in lung cancer associates with hypoxic cell survival and correlates with progression to chemotherapy resistance. Cancer Res. Apr 15 2012;72(8):2140-50. doi:10.1158/0008-5472.Can-11-3940
34. Arzoine L, Zilberberg N, Ben-Romano R, Shoshan-Barmatz V. Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity. J Biol Chem. Feb 6 2009;284(6):3946-55. doi:10.1074/jbc.M803614200
35. Berra E, Ginouvès A, Pouysségur J. The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Rep. Jan 2006;7(1):41-5. doi:10.1038/sj.embor.7400598
36. Jokilehto T, Jaakkola PM. The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med. Apr 2010;14(4):758-70. doi:10.1111/j.1582-4934.2010.01030.x
37. Koivunen P, Hirsilä M, Günzler V, Kivirikko KI, Myllyharju J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem. Mar 12 2004;279(11):9899-904. doi:10.1074/jbc.M312254200
38. Dayan F, Roux D, Brahimi-Horn MC, Pouyssegur J, Mazure NM. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res. Apr 1 2006;66(7):3688-98. doi:10.1158/0008-5472.Can-05-4564
39. Roy R, Yang J, Moses MA. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J Clin Oncol. Nov 1 2009;27(31):5287-97. doi:10.1200/jco.2009.23.5556
40. Mohan R, Chintala SK, Jung JC, et al. Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration. J Biol Chem. Jan 18 2002;277(3):2065-72. doi:10.1074/jbc.M107611200
41. Doi K, Akaike T, Fujii S, et al. Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br J Cancer. Aug 1999;80(12):1945-54. doi:10.1038/sj.bjc.6690624
42. Torisu-Itakura H, Furue M, Kuwano M, Ono M. Co-expression of thymidine phosphorylase and heme oxygenase-1 in macrophages in human malignant vertical growth melanomas. Jpn J Cancer Res. Sep 2000;91(9):906-10. doi:10.1111/j.1349-7006.2000.tb01033.x
43. Hara E, Takahashi K, Tominaga T, et al. Expression of heme oxygenase and inducible nitric oxide synthase mRNA in human brain tumors. Biochem Biophys Res Commun. Jul 5 1996;224(1):153-8. doi:10.1006/bbrc.1996.0999
44. Sunamura M, Duda DG, Ghattas MH, et al. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer. Angiogenesis. 2003;6(1):15-24. doi:10.1023/a:1025803600840
45. Panchenko MV, Farber HW, Korn JH. Induction of heme oxygenase-1 by hypoxia and free radicals in human dermal fibroblasts. Am J Physiol Cell Physiol. Jan 2000;278(1):C92-c101. doi:10.1152/ajpcell.2000.278.1.C92
46. Tsutsumi S, Yanagawa T, Shimura T, Kuwano H, Raz A. Autocrine motility factor signaling enhances pancreatic cancer metastasis. Clin Cancer Res. Nov 15 2004;10(22):7775-84. doi:10.1158/1078-0432.Ccr-04-1015
47. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. Jun 2002;2(6):442-54. doi:10.1038/nrc822
48. Funasaka T, Yanagawa T, Hogan V, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. Faseb J. Sep 2005;19(11):1422-30. doi:10.1096/fj.05-3699com
49. Gessi S, Merighi S, Sacchetto V, Simioni C, Borea PA. Adenosine receptors and cancer. Biochim Biophys Acta. May 2011;1808(5):1400-12. doi:10.1016/j.bbamem.2010.09.020
50. Fredholm BB. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ. Jul 2007;14(7):1315-23. doi:10.1038/sj.cdd.4402132
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Jan 9, 2026
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The gene expression alterations in chronic hypoxic PANC-1 pancreatic cancer cell line. Pharm Pract (Granada) [Internet]. 2026 Jan. 9 [cited 2026 Jan. 25];23(4):1-8. Available from: https://www.pharmacypractice.org/index.php/pp/article/view/3238
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How to Cite
1.
The gene expression alterations in chronic hypoxic PANC-1 pancreatic cancer cell line. Pharm Pract (Granada) [Internet]. 2026 Jan. 9 [cited 2026 Jan. 25];23(4):1-8. Available from: https://www.pharmacypractice.org/index.php/pp/article/view/3238