Curcumin inhibits hypoxia-induced epithelial‑mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway

Cao,Lei; Xiao,Xue; Lei,Jianjun; Duan,Wanxing; Ma,Qingyong; Li,Wei

doi:10.3892/or.2016.4709

Curcumin inhibits hypoxia-induced epithelial‑mesenchymal transition in pancreatic cancer cells via suppression of the hedgehog signaling pathway

Authors:
- Lei Cao
- Xue Xiao
- Jianjun Lei
- Wanxing Duan
- Qingyong Ma
- Wei Li
View Affiliations

Affiliations: Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: March 28, 2016 https://doi.org/10.3892/or.2016.4709
Pages: 3728-3734

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hypoxic microenvironment, a common feature of pancreatic cancer, is associated with tumor proliferation, metastasis and epithelial-mesenchymal transition (EMT) changes. In recent years, many natural agents, including curcumin, have been proven to possess the ability to inhibit the progression of pancreatic cancer. However, whether curcumin is able to suppress hypoxia-induced pancreatic cancer progression and the underlying mechanisms are still not fully elucidated. The aim of the present study was to evaluate whether curcumin affects hypoxia-induced EMT and the activation of Hh signaling pathway in pancreatic cancer. The human pancreatic cancer cell line Panc-1, was treated with hypoxic condition and curcumin. Cell proliferation was assessed by the MTT assay. Wound healing assay and transwell invasion assay were used to detect the migratory and invasive activity of cancer cells. The EMT-related factors, E-cadherin, N-cadherin, vimentin were detected by QT-PCR, western blot analysis and immunofluorescence staining. The Hh signaling-related factors, SHH, SMO and GLI1 were detected by western blot analysis. The results of present study showed that curcumin could not only inhibit the hypoxia-induced cell proliferation, migration and invasion in pancreatic cancer, but also mediate the expression of EMT-related factors. In addition, curcumin remarkably inhibited hypoxia-mediated activation of Hh signaling pathway. Taken together, these data indicate that curcumin plays an important role in suppressing hypoxia-induced pancreatic cancer metastasis by inhibiting the Hh signaling pathway. Curcumin might be a potential candidate for chemoprevention of this severe disease.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Sarkar FH, Banerjee S and Li Y: Pancreatic cancer: Pathogenesis, prevention and treatment. Toxicol Appl Pharmacol. 224:326–336. 2007. View Article : Google Scholar
3	Castellanos EH, Cardin DB and Berlin JD: Treatment of early-stage pancreatic cancer. Oncology (Williston Park). 25:182–189. 2011.
4	Chang J and Erler J: Hypoxia-mediated metastasis. Adv Exp Med Biol. 772:55–81. 2014. View Article : Google Scholar
5	Lei J, Ma J, Ma Q, Li X, Liu H, Xu Q, Duan W, Sun Q, Xu J, Wu Z, et al: Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner. Mol Cancer. 12:662013. View Article : Google Scholar : PubMed/NCBI
6	Duan W, Chang Y, Li R, Xu Q, Lei J, Yin C, Li T, Wu Y, Ma Q and Li X: Curcumin inhibits hypoxia inducible factor-1α-induced epithelial-mesenchymal transition in HepG2 hepatocellular carcinoma cells. Mol Med Rep. 10:2505–2510. 2014.PubMed/NCBI
7	Li W, Ma Q, Liu J, Han L, Ma G, Liu H, Shan T, Xie K and Wu E: Hyperglycemia as a mechanism of pancreatic cancer metastasis. Front Biosci (Landmark Ed). 17:1761–1774. 2012. View Article : Google Scholar
8	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
9	Pirozzi G, Tirino V, Camerlingo R, Franco R, La Rocca A, Liguori E, Martucci N, Paino F, Normanno N and Rocco G: Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One. 6:e215482011. View Article : Google Scholar
10	Shanmugam MK, Rane G, Kanchi MM, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Tan BK, Kumar AP and Sethi G: The multifaceted role of curcumin in cancer prevention and treatment. Molecules. 20:2728–2769. 2015. View Article : Google Scholar : PubMed/NCBI
11	Kocaadam B and Sanlier N: Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit Rev Food Sci Nutr. 0:Nov 3–2015.Epub ahead of print.
12	Sun XD, Liu XE and Huang DS: Curcumin reverses the epithelial-mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol Rep. 29:2401–2407. 2013.PubMed/NCBI
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
14	Nieto MA: Epithelial-mesenchymal transitions in development and disease: Old views and new perspectives. Int J Dev Biol. 53:1541–1547. 2009. View Article : Google Scholar : PubMed/NCBI
15	Spivak-Kroizman TR, Hostetter G, Posner R, Aziz M, Hu C, Demeure MJ, Von Hoff D, Hingorani SR, Palculict TB, Izzo J, et al: Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer. Cancer Res. 73:3235–3247. 2013. View Article : Google Scholar : PubMed/NCBI
16	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar : PubMed/NCBI
17	Liu H, Ma Q, Xu Q, Lei J, Li X, Wang Z and Wu E: Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. Curr Pharm Des. 18:2395–2403. 2012. View Article : Google Scholar : PubMed/NCBI
18	Vasseur S, Tomasini R, Tournaire R and Iovanna JL: Hypoxia induced tumor metabolic switch contributes to pancreatic cancer aggressiveness. Cancers (Basel). 2:2138–2152. 2010. View Article : Google Scholar
19	Ghattass K, Assah R, El-Sabban M and Gali-Muhtasib H: Targeting hypoxia for sensitization of tumors to radio- and chemotherapy. Curr Cancer Drug Targets. 13:670–685. 2013. View Article : Google Scholar : PubMed/NCBI
20	Liao D and Johnson RS: Hypoxia: A key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26:281–290. 2007. View Article : Google Scholar : PubMed/NCBI
21	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
22	Lei J, Huo X, Duan W, Xu Q, Li R, Ma J, Li X, Han L, Li W, Sun H, et al: α-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion. Cancer Lett. 347:129–138. 2014. View Article : Google Scholar : PubMed/NCBI
23	Li W, Ma J, Ma Q, Li B, Han L, Liu J, Xu Q, Duan W, Yu S, Wang F, et al: Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway. Curr Med Chem. 20:4185–4194. 2013. View Article : Google Scholar
24	Youns M and Fathy GM: Upregulation of extrinsic apoptotic pathway in curcumin-mediated antiproliferative effect on human pancreatic carcinogenesis. J Cell Biochem. 114:2654–2665. 2013. View Article : Google Scholar : PubMed/NCBI
25	Nagaraju GP, Zhu S, Ko JE, Ashritha N, Kandimalla R, Snyder JP, Shoji M and El-Rayes BF: Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer. Cancer Lett. 357:557–565. 2015. View Article : Google Scholar
26	Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J and Aggarwal BB: Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 67:3853–3861. 2007. View Article : Google Scholar : PubMed/NCBI
27	Bao B, Ali S, Ahmad A, Azmi AS, Li Y, Banerjee S, Kong D, Sethi S, Aboukameel A, Padhye SB, et al: Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS One. 7:e501652012. View Article : Google Scholar : PubMed/NCBI
28	Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, Al-Kofide A and Aboussekhra A: Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. Mol Carcinog. 49:302–314. 2010.
29	Slusarz A, Shenouda NS, Sakla MS, Drenkhahn SK, Narula AS, MacDonald RS, Besch-Williford CL and Lubahn DB: Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer. Cancer Res. 70:3382–3390. 2010. View Article : Google Scholar : PubMed/NCBI
30	Mohapatra P, Satapathy SR, Siddharth S, Das D, Nayak A and Kundu CN: Resveratrol and curcumin synergistically induces apoptosis in cigarette smoke condensate transformed breast epithelial cells through a p21^Waf1/Cip1 mediated inhibition of Hh-Gli signaling. Int J Biochem Cell Biol. 66:75–84. 2015. View Article : Google Scholar : PubMed/NCBI
31	Guan X: Cancer metastases: Challenges and opportunities. Acta Pharm Sin B. 5:402–418. 2015. View Article : Google Scholar : PubMed/NCBI
32	Liu ZJ, Semenza GL and Zhang HF: Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B. 16:32–43. 2015. View Article : Google Scholar : PubMed/NCBI
33	Li W, Cao L, Han L, Xu Q and Ma Q: Superoxide dismutase promotes the epithelial-mesenchymal transition of pancreatic cancer cells via activation of the H₂O₂/ERK/NF-κB axis. Int J Oncol. 46:2613–2620. 2015.