Stimulated upregulation of HO‑1 is associated with inadequate response of gastric and ovarian cancer cell lines to hyperthermia and cisplatin treatment

Cesna,Vaidotas; Sukovas,Arturas; Jasukaitiene,Aldona; Silkuniene,Giedre; Paskauskas,Saulius; Dambrauskas,Zilvinas; Gulbinas,Antanas

doi:10.3892/ol.2019.10489

Stimulated upregulation of HO‑1 is associated with inadequate response of gastric and ovarian cancer cell lines to hyperthermia and cisplatin treatment

Authors:
- Vaidotas Cesna
- Arturas Sukovas
- Aldona Jasukaitiene
- Giedre Silkuniene
- Saulius Paskauskas
- Zilvinas Dambrauskas
- Antanas Gulbinas
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Affiliations: Department of Surgery, Lithuanian University of Health Sciences, LT‑50161 Kaunas, Lithuania, Department of Obstetrics and Gynaecology, Lithuanian University of Health Sciences, LT‑50161 Kaunas, Lithuania, Institute for Digestive Research, Lithuanian University of Health Sciences, LT‑50161 Kaunas, Lithuania
Published online on: June 18, 2019 https://doi.org/10.3892/ol.2019.10489
Pages: 1961-1968

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Abstract

Heme oxygenase (HO)‑1 is a heat shock protein induced by hyperthermia, responsible for cellular resistance to temperature. The aim of this in vitro study was to clarify the response of gastric and ovarian cancer cells to hyperthermic intraperitoneal chemotherapy, following the modulation of HO‑1 expression. AGS and OVCAR‑3 cells were treated with different temperature regimens, either alone or in combination with an IC50 dose of cisplatin for 1 h. Prior to treatment, HO‑1 expression was silenced by short interfering RNA transfection. In OVCAR‑3 cells, cisplatin increased HO‑1 mRNA expression by 3.73‑fold under normothermia and 2.4‑fold under hyperthermia; furthermore, these factors similarly increased HO‑1 protein expression levels. Exposure to cisplatin under hyperthermia reduced the viability of OVCAR‑3 cells by 36% and HO‑1‑silencing enhanced this effect by 20%. HO‑1‑silencing under normothermia increased apoptotic rates in cisplatin‑treated OVCAR‑3 cells by 2.07‑fold, and hyperthermia enhanced the effect by 3.09‑fold. Semi‑quantitative polymerase chain reaction (PCR) cell analysis indicated that exposure to cisplatin decreased the cell index under normothermia, and that hyperthermia boosted this effect in OVCAR‑3. In AGS cells, only temperature increased cellular HO‑1 levels. Silencing HO‑1 in AGS cells at 37˚C reduced viability by 16% and increased apoptotic rates 2.63‑fold. Hyperthermia did not affect AGS viability; however, apoptosis was increased 6.84‑fold. PCR analysis indicated no additional effects of hyperthermia on the AGS cell index. HO‑1 is induced in cancer cells by different stressors in a variable manner. In tumors with highly inducible HO‑1, prior silencing of this gene could improve the cellular response to hyperthermia and cisplatin.

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1	Shariff U, Seretis C and Youssef H: Management of colorectal cancer patients at high risk of peritoneal metastases. J BUON. 20 (Suppl 1):S71–S79. 2015.PubMed/NCBI
2	Zivanovic O, Chi DS, Filippova O, Randall LM, Bristow RE and O'Cearbhaill RE: It's time to warm up to hyperthermic intraperitoneal chemotherapy for patients with ovarian cancer. Gynecol Oncol. 151:555–561. 2018. View Article : Google Scholar : PubMed/NCBI
3	Yonemura Y, Endou Y, Sasaki T, Hirano M, Mizumoto A, Matsuda T, Takao N, Ichinose M, Miura M and Li Y: Surgical treatment for peritoneal carcinomatosis from gastric cancer. Eur J Surg Oncol. 36:1131–1138. 2010. View Article : Google Scholar : PubMed/NCBI
4	Stewart JH IV, Shen P and Levine EA: Intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: Current status and future directions. Ann Surg Oncol. 12:765–777. 2005. View Article : Google Scholar : PubMed/NCBI
5	Stirrups R: HIPEC improves survival in stage III epithelial ovarian cancer. Lancet Oncol. 19:e1382018. View Article : Google Scholar : PubMed/NCBI
6	Tentes AA, Pallas N, Karamveri C, Kyziridis D and Hristakis C: Cytoreduction and HIPEC for peritoneal carcinomatosis of pancreatic cancer. J BUON. 23:482–487. 2018.PubMed/NCBI
7	Tonello M, Ortega-Perez G, Alonso-Casado O, Torres-Mesa P, Guiñez G and Gonzalez-Moreno S: Peritoneal carcinomatosis arising from rectal or colonic adenocarcinoma treated with cytoreductive surgery (CRS) hyperthermic intraperitoneal chemotherapy (HIPEC): Two different diseases. Clin Transl Oncol. 20:1268–1273. 2018. View Article : Google Scholar : PubMed/NCBI
8	Jacquet P and Sugarbaker PH: Peritoneal-plasma barrier. Cancer Treat Res. 82:53–63. 1996. View Article : Google Scholar : PubMed/NCBI
9	Markman M: Intraperitoneal chemotherapy in the management of malignant disease. Expert Rev Anticancer Ther. 1:142–148. 2001. View Article : Google Scholar : PubMed/NCBI
10	Helm CW: The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer. Oncologist. 14:683–694. 2009. View Article : Google Scholar : PubMed/NCBI
11	Dovern E, de Hingh IH, Verwaal VJ, van Driel WJ and Nienhuijs SW: Hyperthermic intraperitoneal chemotherapy added to the treatment of ovarian cancer. a review of achieved results and complications. Eur J Gynaecol Oncol. 31:256–261. 2010.PubMed/NCBI
12	Zhu Y, Hanna N, Boutros C and Alexander HR Jr: Assessment of clinical benefit and quality of life in patients undergoing cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for management of peritoneal metastases. J Gastrointest Oncol. 4:62–71. 2013.PubMed/NCBI
13	van de Vaart PJ, van der Vange N, Zoetmulder FA, van Goethem AR, van Tellingen O, ten Bokkel Huinink WW, Beijnen JH, Bartelink H and Begg AC: Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines. Eur J Cancer. 34:148–154. 1998. View Article : Google Scholar : PubMed/NCBI
14	Yan TD, Cao CQ and Munkholm-Larsen S: A pharmacological review on intraperitoneal chemotherapy for peritoneal malignancy. World J Gastrointest Oncol. 2:109–116. 2010. View Article : Google Scholar : PubMed/NCBI
15	Kimura E and Howell SB: Analysis of the cytotoxic interaction between cisplatin and hyperthermia in a human ovarian carcinoma cell line. Cancer Chemother Pharmacol. 32:419–424. 1993. View Article : Google Scholar : PubMed/NCBI
16	Sukovas A, Cesna V, Jasukaitiene A, Barauskas G, Nadisauskiene RJ, Dambrauskas Z, Paskauskas S and Gulbinas A: Response of OVCAR-3 cells to cisplatin and hyperthermia: does hyperthermia really matter? Anticancer Res. 37:5011–5018. 2017.PubMed/NCBI
17	Leung AW, Hung SS, Backstrom I, Ricaurte D, Kwok B, Poon S, McKinney S, Segovia R, Rawji J, Qadir MA, et al: Combined use of gene expression modeling and siRNA screening identifies genes and pathways which enhance the activity of cisplatin when added at no effect levels to non-small cell lung cancer cells in vitro. PLoS One. 11:e01506752016. View Article : Google Scholar : PubMed/NCBI
18	Skowron MA, Niegisch G, Albrecht P, van Koeveringe G, Romano A, Albers P, Schulz WA and Hoffmann MJ: Various mechanisms involve the nuclear factor (erythroid-derived 2)-like (NRF2) to achieve cytoprotection in long-term cisplatin-treated urothelial carcinoma cell lines. Int J Mol Sci. 18(pii): E16802017. View Article : Google Scholar : PubMed/NCBI
19	Kumar S, Stokes J III, Singh UP, Scissum Gunn K, Acharya A, Manne U and Mishra M: Targeting Hsp70: a possible therapy for cancer. Cancer Lett. 374:156–166. 2016. View Article : Google Scholar : PubMed/NCBI
20	Thul PJ, Åkesson L, Wiking M, Mahdessian D, Geladaki A, Ait Blal H, Alm T, Asplund A, Björk L, Breckels LM, et al: A subcellular map of the human proteome. Science. 356(pii): eaal33212017. View Article : Google Scholar : PubMed/NCBI
21	Rushworth SA and O'Connell MA: Haem oxygenase-1 in inflammation. Biochem Soc Trans. 32:1093–1094. 2004. View Article : Google Scholar : PubMed/NCBI
22	Nemmiche S, Chabane-Sari D, Kadri M and Guiraud P: Cadmium-induced apoptosis in the BJAB human B cell line: involvement of PKC/ERK1/2/JNK signaling pathways in HO-1 expression. Toxicology. 300:103–111. 2012. View Article : Google Scholar : PubMed/NCBI
23	Shibahara S, Müller RM and Taguchi H: Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem. 262:12889–12892. 1987.PubMed/NCBI
24	Vile GF, Basu-Modak S, Waltner C and Tyrrell RM: Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts. Proc Natl Acad Sci USA. 91:2607–2610. 1994. View Article : Google Scholar : PubMed/NCBI
25	Yang RC, Chang CY, Lu TS and Chen SC: Effects of hyperthermia pretreatment on expression of heme oxygenase-1 and nitric oxide synthase in rats subjected to experimental anaphylactic shock. Chin J Physiol. 48:193–199. 2005.PubMed/NCBI
26	Berberat PO, Dambrauskas Z, Gulbinas A, Giese T, Giese N, Künzli B, Autschbach F, Meuer S, Büchler MW and Friess H: Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment. Clin Cancer Res. 11:3790–3798. 2005. View Article : Google Scholar : PubMed/NCBI
27	Schneider CA, Rasband WS and Eliceiri KW: NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 9:671–675. 2012. View Article : Google Scholar : PubMed/NCBI
28	Ke N, Wang X, Xu X and Abassi YA: The xCELLigence system for real-time and label-free monitoring of cell viability. Methods Mol Biol. 740:33–43. 2011. View Article : Google Scholar : PubMed/NCBI
29	Kang LY, Mok KT, Liu SI, Tsai CC, Wang BW, Chen IS, Chen YC, Chang BM and Chou NH: Intraoperative hyperthermic intraperitoneal chemotherapy as adjuvant chemotherapy for advanced gastric cancer patients with serosal invasion. J Chin Med Assoc. 76:425–431. 2013. View Article : Google Scholar : PubMed/NCBI
30	Halkia E and Spiliotis J: The role of cytoreductive surgery and HIPEC in epithelial ovarian cancer. J BUON. 20 (Suppl 1):S12–S28. 2015.PubMed/NCBI
31	Cesna V, Sukovas A, Jasukaitiene A, Naginiene R, Barauskas G, Dambrauskas Z, Paskauskas S and Gulbinas A: Narrow line between benefit and harm: additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells. World J Gastroenterol. 24:1072–1083. 2018. View Article : Google Scholar : PubMed/NCBI
32	Papatheodorou I, Fonseca NA, Keays M, Tang YA, Barrera E, Bazant W, Burke M, Füllgrabe A, Fuentes AM, George N, et al: Expression Atlas: gene and protein expression across multiple studies and organisms. Nucleic Acids Res. 46(D1): D246–D251. 2018. View Article : Google Scholar : PubMed/NCBI
33	Nitti M, Piras S, Marinari UM, Moretta L, Pronzato MA and Furfaro AL: HO-1 induction in cancer progression: a matter of cell adaptation. Antioxidants (Basel). 6(pii): E292017. View Article : Google Scholar : PubMed/NCBI
34	Chau LY: Heme oxygenase-1: Emerging target of cancer therapy. J Biomed Sci. 22:222015. View Article : Google Scholar : PubMed/NCBI
35	Wang TY, Liu CL, Chen MJ, Lee JJ, Pun PC and Cheng SP: Expression of haem oxygenase-1 correlates with tumour aggressiveness and BRAF V600E expression in thyroid cancer. Histopathology. 66:447–456. 2015. View Article : Google Scholar : PubMed/NCBI
36	Loboda A, Jozkowicz A and Dulak J: HO-1/CO system in tumor growth, angiogenesis and metabolism-Targeting HO-1 as an anti-tumor therapy. Vascul Pharmacol. 74:11–22. 2015. View Article : Google Scholar : PubMed/NCBI
37	Was H, Dulak J and Jozkowicz A: Heme oxygenase-1 in tumor biology and therapy. Curr Drug Targets. 11:1551–1570. 2010. View Article : Google Scholar : PubMed/NCBI
38	Becker JC, Fukui H, Imai Y, Sekikawa A, Kimura T, Yamagishi H, Yoshitake N, Pohle T, Domschke W and Fujimori T: Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer. Scand J Gastroenterol. 42:852–858. 2007. View Article : Google Scholar : PubMed/NCBI
39	Goodman AI, Choudhury M, da Silva JL, Schwartzman ML and Abraham NG: Overexpression of the heme oxygenase gene in renal cell carcinoma. Proc Soc Exp Biol Med. 214:54–61. 1997. View Article : Google Scholar : PubMed/NCBI
40	Maines MD and Abrahamsson PA: Expression of heme oxygenase-1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution. Urology. 47:727–733. 1996. View Article : Google Scholar : PubMed/NCBI
41	Lv X, Song DM, Niu YH and Wang BS: Inhibition of heme oxygenase-1 enhances the chemosensitivity of laryngeal squamous cell cancer Hep-2 cells to cisplatin. Apoptosis. 21:489–501. 2016. View Article : Google Scholar : PubMed/NCBI
42	Jeon WK, Hong HY, Seo WC, Lim KH, Lee HY, Kim WJ, Song SY and Kim BC: Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition. Biochem Biophys Res Commun. 420:288–292. 2012. View Article : Google Scholar : PubMed/NCBI
43	Gozzelino R, Jeney V and Soares MP: Mechanisms of cell protection by heme oxygenase-1. Annu Rev Pharmacol Toxicol. 50:323–354. 2010. View Article : Google Scholar : PubMed/NCBI
44	Ewing JF, Haber SN and Maines MD: Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: Hyperthermia causes rapid induction of mRNA and protein. J Neurochem. 58:1140–1149. 1992. View Article : Google Scholar : PubMed/NCBI
45	Choi AM and Alam J: Heme oxygenase-1: Function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 15:9–19. 1996. View Article : Google Scholar : PubMed/NCBI
46	Zhao Z, Xu Y, Lu J, Xue J and Liu P: High expression of HO-1 predicts poor prognosis of ovarian cancer patients and promotes proliferation and aggressiveness of ovarian cancer cells. Clin Transl Oncol. 20:491–499. 2018. View Article : Google Scholar : PubMed/NCBI
47	Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, Beppu T, Shibahara S, Ogawa M and Maeda H: Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br J Cancer. 80:1945–1954. 1999. View Article : Google Scholar : PubMed/NCBI
48	Nuhn P, Künzli BM, Hennig R, Mitkus T, Ramanauskas T, Nobiling R, Meuer SC, Friess H and Berberat PO: Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo. Mol Cancer. 8:372009. View Article : Google Scholar : PubMed/NCBI
49	Kongpetch S, Kukongviriyapan V, Prawan A, Senggunprai L, Kukongviriyapan U and Buranrat B: Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. PLoS One. 7:e349942012. View Article : Google Scholar : PubMed/NCBI
50	Gueron G, Giudice J, Valacco P, Paez A, Elguero B, Toscani M, Jaworski F, Leskow FC, Cotignola J, Marti M, et al: Heme-oxygenase-1 implications in cell morphology and the adhesive behavior of prostate cancer cells. Oncotarget. 5:4087–4102. 2014. View Article : Google Scholar : PubMed/NCBI
51	Barry MA, Behnke CA and Eastman A: Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia. Biochem Pharmacol. 40:2353–2362. 1990. View Article : Google Scholar : PubMed/NCBI
52	Geske FJ, Lieberman R, Strange R and Gerschenson LE: Early stages of p53-induced apoptosis are reversible. Cell Death Differ. 8:182–191. 2001. View Article : Google Scholar : PubMed/NCBI