Bisdemethoxycurcumin suppresses human osteosarcoma U‑2 OS cell migration and invasion via affecting the PI3K/Akt/NF‑κB, PI3K/Akt/GSK3β and MAPK signaling pathways <em>in vitro</em>

Ma,Yi-Shih; Peng,Shu-Fen; Wu,Rick Sai-Chuen; Chueh,Fu-Shin; Huang,Wen-Wen; Chen,Po-Yuan; Kuo,Chao-Lin; Huang,An-Cheng; Liao,Ching-Lung; Hsia,Te-Chun

doi:10.3892/or.2022.8425

Bisdemethoxycurcumin suppresses human osteosarcoma U‑2 OS cell migration and invasion via affecting the PI3K/Akt/NF‑κB, PI3K/Akt/GSK3β and MAPK signaling pathways in vitro

Authors:
- Yi-Shih Ma
- Shu-Fen Peng
- Rick Sai-Chuen Wu
- Fu-Shin Chueh
- Wen-Wen Huang
- Po-Yuan Chen
- Chao-Lin Kuo
- An-Cheng Huang
- Ching-Lung Liao
- Te-Chun Hsia
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Affiliations: School of Chinese Medicine for Post‑Baccalaureate, College of Medicine, I‑Shou University, Kaohsiung 82445, Taiwan, R.O.C., Department of Biological Science and Technology, China Medical University, Taichung 406040, Taiwan, R.O.C., Department of Anesthesiology, China Medical University Hospital, Taichung 404332, Taiwan, R.O.C., Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 413305, Taiwan, R.O.C., Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 406040, Taiwan, R.O.C., Department of Nursing, St. Mary's Junior College of Medicine, Nursing and Management, Yilan 26647, Taiwan, R.O.C., School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 406040, Taiwan, R.O.C., Department of Respiratory Therapy, China Medical University, Taichung 404333, Taiwan, R.O.C.
Published online on: October 12, 2022 https://doi.org/10.3892/or.2022.8425
Article Number: 210

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Abstract

The metastasis of human osteosarcoma (OS) shows a difficult‑to‑treat clinical scenario and results in decreased quality of life and diminished survival rates. Finding or developing novel treatments to improve the life quality of patients is urgent. Bisdemethoxycurcumin (BDMC), a natural product, was obtained from the rhizome of turmeric (Curcuma longa) and exerts antitumor activities in numerous human cancer cell lines. At present, there is no study showing BDMC effects on OS cell migration and invasion. In the present study, the effects of BDMC on cell migration and invasion of OS U‑2 OS cells were investigated in vitro. Cell viability and proliferation were measured by flow cytometric and MTT assays, respectively. Cell motility, MMP‑2 and ‑9 activity, and cell migration and invasion were assayed by scratch wound healing, gelatin zymography, and Transwell chamber assays, respectively. The protein expression levels were measured by western blotting. BDMC at 20 and 40 µM significantly reduced total cell viability, and BDMC at 5 and 10 µM significantly inhibited cell motility in U‑2 OS cells. BDMC significantly suppressed the activities of MMP‑2 and MMP‑9 in U‑2 OS cells. BDMC suppressed cell invasion and migration after 24 h treatment in U‑2 OS cells, and these effects were in a dose‑dependently manner. Results from western blotting indicated that BDMC significantly decreased the protein expression levels of PI3K/Akt/NF‑κB, PI3K/Akt/GSK3β, and MAPK pathway in U‑2 OS cells. Furthermore, BDMC inhibited uPA, MMP‑2, MMP‑9, MMP‑13, N‑cadherin, VE‑cadherin, and vimentin but increased E‑cadherin in U‑2 OS cells. Based on these observations, it was suggested that BDMC may be a potential candidate against migration and invasion of human OS cells in the future.

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1	Taran SJ, Taran R and Malipatil NB: Pediatric osteosarcoma: An updated review. Indian J Med Paediatr Oncol. 38:33–43. 2017. View Article : Google Scholar : PubMed/NCBI
2	Deng Z, Liu X, Jin J, Xu H, Gao Q, Wang Y and Zhao J: Histone deacetylase inhibitor trichostatin a promotes the apoptosis of osteosarcoma cells through p53 signaling pathway activation. Int J Biol Sci. 12:1298–1308. 2016. View Article : Google Scholar : PubMed/NCBI
3	Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K, Bhattacharya S and Basu A: Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep. 6:219032016. View Article : Google Scholar : PubMed/NCBI
4	Lu J, Song G, Tang Q, Zou C, Han F, Zhao Z, Yong B, Yin J, Xu H, Xie X, et al: IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling. J Clin Invest. 125:1839–1856. 2015. View Article : Google Scholar : PubMed/NCBI
5	Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, et al: Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 20:776–790. 2002. View Article : Google Scholar : PubMed/NCBI
6	Wang JY, Wu PK, Chen PC, Yen CC, Hung GY, Chen CF, Hung SC, Tsai SF, Liu CL, Chen TH and Chen WM: Manipulation therapy prior to diagnosis induced primary osteosarcoma metastasis-from clinical to basic research. PLoS One. 9:e965712014. View Article : Google Scholar : PubMed/NCBI
7	Mercadante S: Malignant bone pain: Pathophysiology and treatment. Pain. 69:1–18. 1997. View Article : Google Scholar : PubMed/NCBI
8	Mercadante S and Fulfaro F: Management of painful bone metastases. Curr Opin Oncol. 19:308–314. 2007. View Article : Google Scholar : PubMed/NCBI
9	Harris JD: Management of expected and unexpected opioid-related side effects. Clin J Pain. 24 (Suppl 10):S8–S13. 2008. View Article : Google Scholar : PubMed/NCBI
10	Weber M and Huber C: Documentation of severe pain, opioid doses, and opioid-related side effects in outpatients with cancer: A retrospective study. J Pain Symptom Manage. 17:49–54. 1999. View Article : Google Scholar : PubMed/NCBI
11	Yi XJ, Zhao YH, Qiao LX, Jin CL, Tian J and Li QS: Aberrant Wnt/β-catenin signaling and elevated expression of stem cell proteins are associated with osteosarcoma side population cells of high tumorigenicity. Mol Med Rep. 12:5042–5048. 2015. View Article : Google Scholar : PubMed/NCBI
12	Gupta GP and Massagué J: Cancer metastasis: Building a framework. Cell. 127:679–695. 2006. View Article : Google Scholar : PubMed/NCBI
13	Talmadge JE and Fidler IJ: AACR centennial series: The biology of cancer metastasis: Historical perspective. Cancer Res. 70:5649–5669. 2010. View Article : Google Scholar : PubMed/NCBI
14	Bacac M and Stamenkovic I: Metastatic cancer cell. Annu Rev Pathol. 3:221–247. 2008. View Article : Google Scholar : PubMed/NCBI
15	Chambers AF, Groom AC and MacDonald IC: Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2:563–572. 2002. View Article : Google Scholar : PubMed/NCBI
16	Duffy MJ, McGowan PM and Gallagher WM: Cancer invasion and metastasis: Changing views. J Pathol. 214:283–293. 2008. View Article : Google Scholar : PubMed/NCBI
17	Fidler IJ: The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 3:453–458. 2003. View Article : Google Scholar : PubMed/NCBI
18	Steeg PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
19	Tarin D: Cell and tissue interactions in carcinogenesis and metastasis and their clinical significance. Semin Cancer Biol. 21:72–82. 2011. View Article : Google Scholar : PubMed/NCBI
20	Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R and Kaur G: Matrix metalloproteinases and cancer-roles in threat and therapy. Asian Pac J Cancer Prev. 15:1085–1091. 2014. View Article : Google Scholar : PubMed/NCBI
21	Yilmaz M, Christofori G and Lehembre F: Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med. 13:535–541. 2007. View Article : Google Scholar : PubMed/NCBI
22	Nieto MA, Huang RY, Jackson RA and Thiery JP: EMT: 2016. Cell. 166:21–45. 2016. View Article : Google Scholar : PubMed/NCBI
23	Kansara M and Thomas DM: Molecular pathogenesis of osteosarcoma. DNA Cell Biol. 26:1–18. 2007. View Article : Google Scholar : PubMed/NCBI
24	Jayaprakasha GK, Jaganmohan Rao L and Sakariah KK: Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Chem. 98:720–724. 2006. View Article : Google Scholar
25	Shishodia S: Molecular mechanisms of curcumin action: Gene expression. Biofactors. 39:37–55. 2013. View Article : Google Scholar : PubMed/NCBI
26	Masuda T, Hidaka K, Shinohara A, Maekawa T, Takeda Y and Yamaguchi H: Chemical studies on antioxidant mechanism of curcuminoid: Analysis of radical reaction products from curcumin. J Agric Food Chem. 47:71–77. 1999. View Article : Google Scholar : PubMed/NCBI
27	Li YB, Gao JL, Zhong ZF, Hoi PM, Lee SM and Wang YT: Bisdemethoxycurcumin suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways. Pharmacol Rep. 65:700–709. 2013. View Article : Google Scholar : PubMed/NCBI
28	Luo C, Du Z, Wei X, Chen G and Fu Z: Bisdemethoxycurcumin attenuates gastric adenocarcinoma growth by inducing mitochondrial dysfunction. Oncol Lett. 9:270–274. 2015. View Article : Google Scholar : PubMed/NCBI
29	Hongtao C, Youling F, Fang H, Huihua P, Jiying Z and Jun Z: Curcumin alleviates ischemia reperfusion-induced late kidney fibrosis through the APPL1/Akt signaling pathway. J Cell Physiol. 233:8588–8596. 2018. View Article : Google Scholar : PubMed/NCBI
30	Liao CL, Chu YL, Lin HY, Chen CY, Hsu MJ, Liu KC, Lai KC, Huang AC and Chung JG: Bisdemethoxycurcumin suppresses migration and invasion of human cervical cancer HeLa cells via inhibition of NF-ĸB, MMP-2 and −9 pathways. Anticancer Res. 38:3989–3997. 2018. View Article : Google Scholar : PubMed/NCBI
31	Xu J, Yang H, Zhou X, Wang H, Gong L and Tang C: Bisdemethoxycurcumin suppresses migration and invasion of highly metastatic 95D lung cancer cells by regulating E-cadherin and vimentin expression, and inducing autophagy. Mol Med Rep. 12:7603–7608. 2015. View Article : Google Scholar : PubMed/NCBI
32	Isfort RJ, Cody DB, Lovell G and Doersen CJ: Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines. Mol Carcinog. 14:170–178. 1995. View Article : Google Scholar : PubMed/NCBI
33	Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, et al: Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 434:907–913. 2005. View Article : Google Scholar : PubMed/NCBI
34	Mancini L, Paul-Clark MJ, Rosignoli G, Hannon R, Martin JE, Macintyre I and Perretti M: Calcitonin and prednisolone display antagonistic actions on bone and have synergistic effects in experimental arthritis. Am J Pathol. 170:1018–1027. 2007. View Article : Google Scholar : PubMed/NCBI
35	Shih YL, Au MK, Liu KL, Yeh MY, Lee CH, Lee MH, Lu HF, Yang JL, Wu RS and Chung JG: Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 32:2400–2413. 2017. View Article : Google Scholar : PubMed/NCBI
36	Chen HY, Yang MD, Chou YC, Ma YS, Peng SF, Liao CL, Chen PY, Hsia TC, Lien JC and Chen CH: Ouabain suppresses cell migration and invasion in human gastric cancer AGS cells through the inhibition of MMP signaling pathways. Anticancer Res. 41:4365–4375. 2021. View Article : Google Scholar : PubMed/NCBI
37	Ma YS, Hsiao YT, Lin JJ, Liao CL, Lin CC and Chung JG: Phenethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC) inhibit human melanoma A375.S2 cell migration and invasion by affecting MAPK signaling pathway in vitro. Anticancer Res. 37:6223–6234. 2017.PubMed/NCBI
38	Siegel R, Ward E, Brawley O and Jemal A: Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 61:212–236. 2011. View Article : Google Scholar : PubMed/NCBI
39	Sporn MB: The war on cancer. Lancet. 347:1377–1381. 1996. View Article : Google Scholar : PubMed/NCBI
40	Roato I, Caldo D, Godio L, D'Amico L, Giannoni P, Morello E, Quarto R, Molfetta L, Buracco P, Mussa A and Ferracini R: Bone invading NSCLC cells produce IL-7: Mice model and human histologic data. BMC Cancer. 10:122010. View Article : Google Scholar : PubMed/NCBI
41	Santini D, Galluzzo S, Zoccoli A, Pantano F, Fratto ME, Vincenzi B, Lombardi L, Gucciardino C, Silvestris N, Riva E, et al: New molecular targets in bone metastases. Cancer Treat Rev. 36 (Suppl 3):S6–S10. 2010. View Article : Google Scholar : PubMed/NCBI
42	Liu Y, Bi T, Shen G, Li Z, Wu G, Wang Z, Qian L and Gao Q: Lupeol induces apoptosis and inhibits invasion in gallbladder carcinoma GBC-SD cells by suppression of EGFR/MMP-9 signaling pathway. Cytotechnology. 68:123–133. 2016. View Article : Google Scholar : PubMed/NCBI
43	Pei H, Yang Y, Cui L, Yang J, Li X, Yang Y and Duan H: Bisdemethoxycurcumin inhibits ovarian cancer via reducing oxidative stress mediated MMPs expressions. Sci Rep. 6:287732016. View Article : Google Scholar : PubMed/NCBI
44	Yodkeeree S, Chaiwangyen W, Garbisa S and Limtrakul P: Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit cancer cell invasion through the down-regulation of MMPs and uPA. J Nutr Biochem. 20:87–95. 2009. View Article : Google Scholar : PubMed/NCBI
45	Toth M, Sohail A and Fridman R: Assessment of gelatinases (MMP-2 and MMP-9) by gelatin zymography. Methods Mol Biol. 878:121–135. 2012. View Article : Google Scholar : PubMed/NCBI
46	Grzelczyk WL, Szemraj J and Józefowicz-Korczyńska M: The matrix metalloproteinase in larynx cancer. Postepy Hig Med Dosw (Online). 70:1190–1197. 2016.PubMed/NCBI
47	Hendrix MJ, Seftor EA, Seftor RE and Fidler IJ: A simple quantitative assay for studying the invasive potential of high and low human metastatic variants. Cancer Lett. 38:137–147. 1987. View Article : Google Scholar : PubMed/NCBI
48	Li YH and Zhu C: A modified Boyden chamber assay for tumor cell transendothelial migration in vitro. Clin Exp Metastasis. 17:423–429. 1999. View Article : Google Scholar : PubMed/NCBI
49	Huang T, Kang W, Cheng AS, Yu J and To KF: The emerging role of Slit-Robo pathway in gastric and other gastro intestinal cancers. BMC Cancer. 15:9502015. View Article : Google Scholar : PubMed/NCBI
50	Yang M and Huang CZ: Mitogen-activated protein kinase signaling pathway and invasion and metastasis of gastric cancer. World J Gastroenterol. 21:11673–11679. 2015. View Article : Google Scholar : PubMed/NCBI
51	Fife CM, McCarroll JA and Kavallaris M: Movers and shakers: Cell cytoskeleton in cancer metastasis. Br J Pharmacol. 171:5507–5523. 2014. View Article : Google Scholar : PubMed/NCBI
52	Koul HK, Pal M and Koul S: Role of p38 MAP kinase signal transduction in solid tumors. Genes Cancer. 4:342–359. 2013. View Article : Google Scholar : PubMed/NCBI
53	Yu Y, Luk F, Yang JL and Walsh WR: Ras/Raf/MEK/ERK pathway is associated with lung metastasis of osteosarcoma in an orthotopic mouse model. Anticancer Res. 31:1147–1152. 2011.PubMed/NCBI
54	Wada T and Penninger JM: Mitogen-activated protein kinases in apoptosis regulation. Oncogene. 23:2838–2849. 2004. View Article : Google Scholar : PubMed/NCBI
55	Wang C, Zhou X, Li W, Li M, Tu T, Ba X, Wu Y, Huang Z, Fan G, Zhou G, et al: Macrophage migration inhibitory factor promotes osteosarcoma growth and lung metastasis through activating the RAS/MAPK pathway. Cancer Lett. 403:271–279. 2017. View Article : Google Scholar : PubMed/NCBI
56	Liu Y, Yuan X, Li W, Cao Q and Shu Y: Aspirin-triggered resolvin D1 inhibits TGF-β1-induced EMT through the inhibition of the mTOR pathway by reducing the expression of PKM2 and is closely linked to oxidative stress. Int J Mol Med. 38:1235–1242. 2016. View Article : Google Scholar : PubMed/NCBI
57	Wang H, Zhang C, Xu L, Zang K, Ning Z, Jiang F, Chi H, Zhu X and Meng Z: Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1α via the PI3K/AKT/mTOR pathway. Oncotarget. 7:20193–20208. 2016. View Article : Google Scholar : PubMed/NCBI
58	Mirzaei S, Saghari S, Bassiri F, Raesi R, Zarrabi A, Hushmandi K, Sethi G and Tergaonkar V: NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial-mesenchymal transition. J Cell Physiol. 237:2770–2795. 2022. View Article : Google Scholar : PubMed/NCBI
59	Pi WS, Cao ZY, Liu JM, Peng AF, Chen WZ, Chen JW, Huang SH and Liu ZL: Potential molecular mechanisms of AURKB in the oncogenesis and progression of osteosarcoma cells: A label-free quantitative proteomics analysis. Technol Cancer Res Treat. 18:15330338198532622018.PubMed/NCBI
60	Akiyama T and Kawasaki Y: Wnt signalling and the actin cytoskeleton. Oncogene. 25:7538–7544. 2006. View Article : Google Scholar : PubMed/NCBI
61	Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, DeCarlo A and Engler JA: Matrix metalloproteinases: A review. Crit Rev Oral Biol Med. 4:197–250. 1993. View Article : Google Scholar : PubMed/NCBI
62	Dutta A, Li J, Lu H, Akech J, Pratap J, Wang T, Zerlanko BJ, FitzGerald TJ, Jiang Z, Birbe R, et al: Integrin αvβ6 promotes an osteolytic program in cancer cells by upregulating MMP2. Cancer Res. 74:1598–1608. 2014. View Article : Google Scholar : PubMed/NCBI
63	Chu K, Cheng CJ, Ye X, Lee YC, Zurita AJ, Chen DT, Yu-Lee LY, Zhang S, Yeh ET, Hu MC, et al: Cadherin-11 promotes the metastasis of prostate cancer cells to bone. Mol Cancer Res. 6:1259–1267. 2008. View Article : Google Scholar : PubMed/NCBI
64	Chang JW, Kang SU, Shin YS, Seo SJ, Kim YS, Yang SS, Lee JS, Moon E, Lee K and Kim CH: Combination of NTP with cetuximab inhibited invasion/migration of cetuximab-resistant OSCC cells: Involvement of NF-κB signaling. Sci Rep. 5:182082015. View Article : Google Scholar : PubMed/NCBI
65	Guarino M, Rubino B and Ballabio G: The role of epithelial-mesenchymal transition in cancer pathology. Pathology. 39:305–318. 2007. View Article : Google Scholar : PubMed/NCBI
66	Yuan Y, Ye HQ and Ren QC: Upregulation of the BDNF/TrKB pathway promotes epithelial-mesenchymal transition, as well as the migration and invasion of cervical cancer. Int J Oncol. 52:461–472. 2018.PubMed/NCBI
67	Cuesta C, Arévalo-Alameda C and Castellano E: The importance of being PI3K in the RAS signaling network. Genes (Basel). 12:10942021. View Article : Google Scholar : PubMed/NCBI
68	Matsuoka H, Tsubaki M, Yamazoe Y, Ogaki M, Satou T, Itoh T, Kusunoki T and Nishida S: Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways. Exp Cell Res. 315:2022–2032. 2009. View Article : Google Scholar : PubMed/NCBI