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Article Open Access

Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer

  • Authors:
    • Nengli Yang
    • Yafeng Liang
    • Pei Yang
    • Fuhai Ji
  • View Affiliations / Copyright

    Affiliations: Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China, Department of Pediatric Intensive Care Unit, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
    Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2611-2619
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    Published online on: March 17, 2017
       https://doi.org/10.3892/or.2017.5514
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Abstract

Tumor hypoxia has been recognized as a characteristic of the tumor microenvironment and promotes metastasis in a variety of types of cancer. However, in lung cancer, the role of hypoxia-inducible factor 1α (HIF-1α) in modulating the cellular response to the inflammation-related microenvironment remains unclear. In the present study, enhanced expression of HIF-1α accompanied by an increased ROS level was observed in lipopolysaccharide (LPS)-stimulated non-small cell lung cancer (NSCLC) cells. In addition, propofol, a general anesthetic, was found to significantly reduce the LPS-induced upregulation of HIF-1α and ROS in a dose-dependent manner. Further study showed that propofol may antagonize the role of LPS in activating HIF-1α through attenuating the protein stability and nuclear localization of HIF-1α. Moreover, knockdown of HIF-1α attenuated expression of mesenchymal marker, vimentin, but promoted the expression of epidermal marker, E-cadherin, in the LPS-treated NSCLC cells. Notably, LPS-induced epithelial-to-mesenchymal transition (EMT) was notably suppressed by propofol treatment. Consistently, a wound healing assay revealed that propofol abrogated LPS-stimulated migration of NSCLC cells while overexpression of HIF-1α reversed the effects of propofol. Similarly, we investigated the influence of propofol on the invasive capability of NSCLC cells. Western blot and RT-PCR analyses indicated that both knockdown of HIF-1α and treatment of propofol attenuated the LPS-activated expression of MMP2 and MMP9 which are necessary for tumor invasion. However, results from the Transwell assay confirmed that propofol also suppressed cell invasion by decreasing HIF-1α expression in the LPS-treated NSCLC cells. Analysis of clinical specimens demonstrated abnormal expression of HIF-1α in NSCLC tissues and a poor prognosis in patients with elevated HIF-1α expression. Thus, the present study suggests a potential strategy for NSCLC by targeting HIF-1α.
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1 

Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC and Harris AL: Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res. 61:7992–7998. 2001.PubMed/NCBI

2 

Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, Gatter KC and Harris AL: Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer. 85:881–890. 2001. View Article : Google Scholar : PubMed/NCBI

3 

Le QT, Chen E, Salim A, Cao H, Kong CS, Whyte R, Donington J, Cannon W, Wakelee H, Tibshirani R, et al: An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers. Clin Cancer Res. 12:1507–1514. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Beutler B: Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 430:257–263. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Pchejetski D, Nunes J, Coughlan K, Lall H, Pitson SM, Waxman J and Sumbayev VV: The involvement of sphingosine kinase 1 in LPS-induced Toll-like receptor 4-mediated accumulation of HIF-1α protein, activation of ASK1 and production of the pro-inflammatory cytokine IL-6. Immunol Cell Biol. 89:268–274. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Liu WT, Jing YY, Yan F, Han ZP, Lai FB, Zeng JX, Yu GF, Fan QM, Li R, Zhao QD, et al: LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells. Cell Adh Migr. 0:1–11. 2016.

7 

Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar : PubMed/NCBI

8 

Rankin EB and Giaccia AJ: Hypoxic control of metastasis. Science. 352:175–180. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ and Semenza GL: Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proc Natl Acad Sci USA. 111:E3234–E3242. 2014. View Article : Google Scholar : PubMed/NCBI

10 

Nagaraju GP, Bramhachari PV, Raghu G and El-Rayes BF: Hypoxia inducible factor-1α: Its role in colorectal carcinogenesis and metastasis. Cancer Lett. 366:11–18. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Tian H, Huang P, Zhao Z, Tang W and Xia J: HIF-1α plays a role in the chemotactic migration of hepatocarcinoma cells through the modulation of CXCL6 expression. Cell Physiol Biochem. 34:1536–1546. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Chen J, Gu Y, Shao Z, Luo J and Tan Z: Propofol protects against hydrogen peroxide-induced oxidative stress and cell dysfunction in human umbilical vein endothelial cells. Mol Cell Biochem. 339:43–54. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Kobayashi K, Yoshino F, Takahashi SS, Todoki K, Maehata Y, Komatsu T, Yoshida K and Lee MC: Direct assessments of the antioxidant effects of propofol medium chain triglyceride/long chain triglyceride on the brain of stroke-prone spontaneously hypertensive rats using electron spin resonance spectroscopy. Anesthesiology. 109:426–435. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Mammoto T, Mukai M, Mammoto A, Yamanaka Y, Hayashi Y, Mashimo T, Kishi Y and Nakamura H: Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Lett. 184:165–170. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Altenburg JD, Harvey KA, McCray S, Xu Z and Siddiqui RA: A novel 2,6-diisopropylphenyl-docosahexaenoamide conjugate induces apoptosis in T cell acute lymphoblastic leukemia cell lines. Biochem Biophys Res Commun. 411:427–432. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Tsuchiya M, Asada A, Arita K, Utsumi T, Yoshida T, Sato EF, Utsumi K and Inoue M: Induction and mechanism of apoptotic cell death by propofol in HL-60 cells. Acta Anaesthesiol Scand. 46:1068–1074. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Wu KC, Yang ST, Hsia TC, Yang JS, Chiou SM, Lu CC, Wu RS and Chung JG: Suppression of cell invasion and migration by propofol are involved in down-regulating matrix metalloproteinase-2 and p38 MAPK signaling in A549 human lung adenocarcinoma epithelial cells. Anticancer Res. 32:4833–4842. 2012.PubMed/NCBI

18 

Kapiszewska M, Cierniak A, Elas M and Lankoff A: Lifespan of etoposide-treated human neutrophils is affected by antioxidant ability of quercetin. Toxicol In Vitro. 21:1020–1030. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Chen MC, Chang WW, Kuan YD, Lin ST, Hsu HC and Lee CH: Resveratrol inhibits LPS-induced epithelial-mesenchymal transition in mouse melanoma model. Innate Immun. 18:685–693. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Huang T, Chen Z and Fang L: Curcumin inhibits LPS-induced EMT through downregulation of NF-κB-Snail signaling in breast cancer cells. Oncol Rep. 29:117–124. 2013.PubMed/NCBI

21 

Yang H, Wang B, Wang T, Xu L, He C, Wen H, Yan J, Su H and Zhu X: Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. PLoS One. 9:e1099802014. View Article : Google Scholar : PubMed/NCBI

22 

Chen S, Zhang M, Xing L, Wang Y, Xiao Y and Wu Y: HIF-1α contributes to proliferation and invasiveness of neuroblastoma cells via SHH signaling. PLoS One. 10:e01211152015. View Article : Google Scholar : PubMed/NCBI

23 

Wilde BR and Ayer DE: Interactions between Myc and MondoA transcription factors in metabolism and tumourigenesis. Br J Cancer. 113:1529–1533. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Wan J, Che Y, Kang N and Wu W: SOCS3 blocks HIF-1α expression to inhibit proliferation and angiogenesis of human small cell lung cancer by downregulating activation of Akt, but not STAT3. Mol Med Rep. 12:83–92. 2015.PubMed/NCBI

25 

Ward C, Langdon SP, Mullen P, Harris AL, Harrison DJ, Supuran CT and Kunkler IH: New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat Rev. 39:171–179. 2013. View Article : Google Scholar : PubMed/NCBI

26 

Bredholt G, Mannelqvist M, Stefansson IM, Birkeland E, Bø TH, Øyan AM, Trovik J, Kalland KH, Jonassen I, Salvesen HB, et al: Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses. Oncotarget. 6:39676–39691. 2015.PubMed/NCBI

27 

Gatenby RA and Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 4:891–899. 2004. View Article : Google Scholar : PubMed/NCBI

28 

Adaramoye OA, Akinwonmi O and Akanni O: Effects of propofol, a sedative-hypnotic drug, on the lipid profile, antioxidant indices, and cardiovascular marker enzymes in wistar rats. ISRN Pharmacol. 2013:2302612013. View Article : Google Scholar : PubMed/NCBI

29 

Braz MG, Braz LG, Freire CM, Lucio LM, Braz JR, Tang G, Salvadori DM and Yeum KJ: Isoflurane and propofol contribute to increasing the antioxidant status of patients during minor elective surgery: A randomized clinical study. Medicine. 94:e12662015. View Article : Google Scholar : PubMed/NCBI

30 

Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ and Maxwell PH: Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem. 275:25733–25741. 2000. View Article : Google Scholar : PubMed/NCBI

31 

Semenza GL, Agani F, Booth G, Forsythe J, Iyer N, Jiang BH, Leung S, Roe R, Wiener C and Yu A: Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int. 51:553–555. 1997. View Article : Google Scholar : PubMed/NCBI

32 

Chachami G, Paraskeva E, Mingot JM, Braliou GG, Görlich D and Simos G: Transport of hypoxia-inducible factor HIF-1alpha into the nucleus involves importins 4 and 7. Biochem Biophys Res Commun. 390:235–240. 2009. View Article : Google Scholar : PubMed/NCBI

33 

Li Q, Zhang L, Han Y, Jiang Z and Wang Q: Propofol reduces MMPs expression by inhibiting NF-κB activity in human MDA-MB-231 cells. Biomed Pharmacother. 66:52–56. 2012. View Article : Google Scholar : PubMed/NCBI

34 

Song J, Shen Y, Zhang J and Lian Q: Mini profile of potential anticancer properties of propofol. PLoS One. 9:e1144402014. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yang N, Liang Y, Yang P and Ji F: Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer. Oncol Rep 37: 2611-2619, 2017.
APA
Yang, N., Liang, Y., Yang, P., & Ji, F. (2017). Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer. Oncology Reports, 37, 2611-2619. https://doi.org/10.3892/or.2017.5514
MLA
Yang, N., Liang, Y., Yang, P., Ji, F."Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer". Oncology Reports 37.5 (2017): 2611-2619.
Chicago
Yang, N., Liang, Y., Yang, P., Ji, F."Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer". Oncology Reports 37, no. 5 (2017): 2611-2619. https://doi.org/10.3892/or.2017.5514
Copy and paste a formatted citation
x
Spandidos Publications style
Yang N, Liang Y, Yang P and Ji F: Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer. Oncol Rep 37: 2611-2619, 2017.
APA
Yang, N., Liang, Y., Yang, P., & Ji, F. (2017). Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer. Oncology Reports, 37, 2611-2619. https://doi.org/10.3892/or.2017.5514
MLA
Yang, N., Liang, Y., Yang, P., Ji, F."Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer". Oncology Reports 37.5 (2017): 2611-2619.
Chicago
Yang, N., Liang, Y., Yang, P., Ji, F."Propofol suppresses LPS-induced nuclear accumulation of HIF-1α and tumor aggressiveness in non-small cell lung cancer". Oncology Reports 37, no. 5 (2017): 2611-2619. https://doi.org/10.3892/or.2017.5514
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