HOXC6 regulates the antitumor effects of pheophorbide a-based photodynamic therapy in multidrug-resistant oral cancer cells

Kim,Soo-A; Lee,Mi Rha; Yoon,Jung-Hoon; Ahn,Sang-Gun

doi:10.3892/ijo.2016.3766

HOXC6 regulates the antitumor effects of pheophorbide a-based photodynamic therapy in multidrug-resistant oral cancer cells

Authors:
- Soo-A Kim
- Mi Rha Lee
- Jung-Hoon Yoon
- Sang-Gun Ahn
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Affiliations: Department of Biochemistry, Oriental Medicine, Dongguk University, Gyeongju 780-714, Republic of Korea, Department of Pathology, College of Dentistry, Chosun University, Gwangju 501-759, Republic of Korea, Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang University, Daejeon 302-120, Republic of Korea
Published online on: November 10, 2016 https://doi.org/10.3892/ijo.2016.3766
Pages: 2421-2430

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Abstract

Photodynamic therapy (PDT) has been considered to be a possible candidate approach for the treatment of multidrug-resistant (MDR) cancer. To investigate the photocytotoxicity of pheophorbide a-based PDT on MDR cells, the intracellular pathways were studied using the human oral cancer FaDu cell line and its paclitaxel-selected subline FaDu-PTX. Pheophorbide a (Pa)-PDT induced significant photocytotoxicity in both FaDu and FaDu-PTX cell lines with cell apoptosis greater in FaDu cells compared to FaDu-PTX cells. We found that Hoxc6 and MDR-1 expression was strongly detected in FaDu-PTX cells compared to FaDu cells. Intriguingly, Pa-PDT effectively reduced Hoxc6 and MDR-1 expression in FaDu-PTX cells. The siRNA for HOXC6 can inhibit the intracellular MDR-1 levels in FaDu-PTX cells and induce the phototoxic effects of Pa-PDT. Furthermore, our in vivo studies showed that the Pa-PDT and HOXC6 siRNA significantly reduce the growth of FaDu-PTX xenograft tumors in C3H mice compared with control- and PTX-treated tumors. Histopathology was also used to confirm this antitumor effect. Pa-PDT may be a potential therapeutic modality for multidrug-resistant cancer, and Hoxc6, as a possible contributor to MDR, may reduce the therapeutic potential in multidrug-resistant oral malignancies.

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1	Gottesman MM, Fojo T and Bates SE: Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat Rev Cancer. 2:48–58. 2002. View Article : Google Scholar : PubMed/NCBI
2	Baguley BC: Multidrug resistance in cancer. Methods Mol Biol. 596:1–14. 2010. View Article : Google Scholar
3	Haimeur A, Conseil G, Deeley RG and Cole SP: The MRP-related and BCRP/ABCG2 multidrug resistance proteins: Biology, substrate specificity and regulation. Curr Drug Metab. 5:21–53. 2004. View Article : Google Scholar : PubMed/NCBI
4	Redmond KM, Wilson TR, Johnston PG and Longley DB: Resistance mechanisms to cancer chemotherapy. Front Biosci. 13:5138–5154. 2008. View Article : Google Scholar : PubMed/NCBI
5	Szakács G, Annereau JP, Lababidi S, Shankavaram U, Arciello A, Bussey KJ, Reinhold W, Guo Y, Kruh GD, Reimers M, et al: Predicting drug sensitivity and resistance: Profiling ABC transporter genes in cancer cells. Cancer Cell. 6:129–137. 2004. View Article : Google Scholar : PubMed/NCBI
6	Deeley RG and Cole SP: Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Lett. 580:1103–1111. 2006. View Article : Google Scholar : PubMed/NCBI
7	Litman T, Druley TE, Stein WD and Bates SE: From MDR to MXR: New understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci. 58:931–959. 2001. View Article : Google Scholar : PubMed/NCBI
8	Baguley BC: Multiple drug resistance mechanisms in cancer. Mol Biotechnol. 46:308–316. 2010. View Article : Google Scholar : PubMed/NCBI
9	Pang A, Au WY and Kwong YL: Caveolin-1 gene is coordinately regulated with the multidrug resistance 1 gene in normal and leukemic bone marrow. Leuk Res. 28:973–977. 2004. View Article : Google Scholar : PubMed/NCBI
10	Kim KJ, Moon SM, Kim SA, Kang KW, Yoon JH and Ahn SG: Transcriptional regulation of MDR-1 by HOXC6 in multidrug-resistant cells. Oncogene. 32:3339–3349. 2013. View Article : Google Scholar
11	Chen J, Keltner L, Christophersen J, Zheng F, Krouse M, Singhal A and Wang SS: New technology for deep light distribution in tissue for phototherapy. Cancer J. 8:154–163. 2002. View Article : Google Scholar : PubMed/NCBI
12	Dolmans DE, Fukumura D and Jain RK: Photodynamic therapy for cancer. Nat Rev Cancer. 3:380–387. 2003. View Article : Google Scholar : PubMed/NCBI
13	Kessel D and Erickson C: Porphyrin photosensitization of multi-drug resistant cell types. Photochem Photobiol. 55:397–399. 1992. View Article : Google Scholar : PubMed/NCBI
14	Lu HL, Syu WJ, Nishiyama N, Kataoka K and Lai PS: Dendrimer phthalocyanine-encapsulated polymeric micelle-mediated photochemical internalization extends the efficacy of photodynamic therapy and overcomes drug-resistance in vivo. J Control Release. 155:458–464. 2011. View Article : Google Scholar : PubMed/NCBI
15	Gulati SC, Lemoli RM, Igarashi T and Atzpodien J: Newer options for treating drug-resistant (MDR+) cancer cells using photoradiation therapy. Leuk Lymphoma. 12:427–433. 1994. View Article : Google Scholar : PubMed/NCBI
16	Yoon HE, Oh SH, Kim SA, Yoon JH and Ahn SG: Pheophorbide a-mediated photodynamic therapy induces autophagy and apoptosis via the activation of MAPKs in human skin cancer cells. Oncol Rep. 31:137–144. 2014.
17	Ahn MY, Yoon HE, Kwon SM, Lee J, Min SK, Kim YC, Ahn SG and Yoon JH: Synthesized pheophorbide a-mediated photo-dynamic therapy induced apoptosis and autophagy in human oral squamous carcinoma cells. J Oral Pathol Med. 42:17–25. 2013. View Article : Google Scholar
18	Ahn MY, Kwon SM, Kim YC, Ahn SG and Yoon JH: Pheophorbide a-mediated photodynamic therapy induces apoptotic cell death in murine oral squamous cell carcinoma in vitro and in vivo. Oncol Rep. 27:1772–1778. 2012.PubMed/NCBI
19	Tang PM, Chan JY, Au SW, Kong SK, Tsui SK, Waye MM, Mak TC, Fong WP and Fung KP: Pheophorbide a, an active compound isolated from Scutellaria barbata, possesses photodynamic activities by inducing apoptosis in human hepatocellular carcinoma. Cancer Biol Ther. 5:1111–1116. 2006. View Article : Google Scholar : PubMed/NCBI
20	Tang PM, Zhang DM, Xuan NH, Tsui SK, Waye MM, Kong SK, Fong WP and Fung KP: Photodynamic therapy inhibits P-glycoprotein mediated multidrug resistance via JNK activation in human hepatocellular carcinoma using the photosensitizer pheophorbide a. Mol Cancer. 8:56–66. 2009. View Article : Google Scholar : PubMed/NCBI
21	Hajri A, Wack S, Meyer C, Smith MK, Leberquier C, Kedinger M and Aprahamian M: In vitro and in vivo efficacy of photofrin and pheophorbide a, a bacteriochlorin, in photodynamic therapy of colonic cancer cells. Photochem Photobiol. 75:140–148. 2002. View Article : Google Scholar : PubMed/NCBI
22	Jin ZH, Miyoshi N, Ishiguro K, Umemura S, Kawabata K, Yumita N, Sakata I, Takaoka K, Udagawa T, Nakajima S, et al: Combination effect of photodynamic and sonodynamic therapy on experimental skin squamous cell carcinoma in C3H/HeN mice. J Dermatol. 27:294–306. 2000. View Article : Google Scholar : PubMed/NCBI
23	Bui-Xuan NH, Tang PM, Wong CK and Fung KP: Photo-activated pheophorbide-a, an active component of Scutellaria barbata, enhances apoptosis via the suppression of ERK-mediated autophagy in the estrogen receptor-negative human breast adeno-carcinoma cells MDA-MB-231. J Ethnopharmacol. 131:95–103. 2010. View Article : Google Scholar : PubMed/NCBI
24	Bodey B, Bodey B Jr, Siegel SE and Kaiser HE: Immunocytochemical detection of the homeobox B3, B4, and C6 gene products in breast carcinomas. Anticancer Res. 20(5A): 3281–3286. 2000.PubMed/NCBI
25	Castronovo V, Kusaka M, Chariot A, Gielen J and Sobel M: Homeobox genes: Potential candidates for the transcriptional control of the transformed and invasive phenotype. Biochem Pharmacol. 47:137–143. 1994. View Article : Google Scholar : PubMed/NCBI
26	Fujiki K, Duerr EM, Kikuchi H, Ng A, Xavier RJ, Mizukami Y, Imamura T, Kulke MH and Chung DC: Hoxc6 is overexpressed in gastrointestinal carcinoids and interacts with JunD to regulate tumor growth. Gastroenterology. 135:907–916. 916.e1–916.e2. 2008. View Article : Google Scholar : PubMed/NCBI
27	Bodey B, Bodey B Jr, Siegel SE, Luck JV and Kaiser HE: Homeobox B3, B4, and C6 gene product expression in osteo-sarcomas as detected by immunocytochemistry. Anticancer Res. 20:2717–2721. 2000.PubMed/NCBI
28	Miller GJ, Miller HL, van Bokhoven A, Lambert JR, Werahera PN, Schirripa O, Lucia MS and Nordeen SK: Aberrant HOXC expression accompanies the malignant phenotype in human prostate. Cancer Res. 63:5879–5888. 2003.PubMed/NCBI
29	McCabe CD, Spyropoulos DD, Martin D and Moreno CS: Genome-wide analysis of the homeobox C6 transcriptional network in prostate cancer. Cancer Res. 68:1988–1996. 2008. View Article : Google Scholar : PubMed/NCBI
30	Grishina IB, Kim SY, Ferrara C, Makarenkova HP and Walden PD: BMP7 inhibits branching morphogenesis in the prostate gland and interferes with Notch signaling. Dev Biol. 288:334–347. 2005. View Article : Google Scholar : PubMed/NCBI
31	Ricort JM and Binoux M: Insulin-like growth factor-binding protein-3 activates a phosphotyrosine phosphatase. Effects on the insulin-like growth factor signaling pathway. J Biol Chem. 277:19448–19454. 2002. View Article : Google Scholar : PubMed/NCBI
32	van der Geer P, Hunter T and Lindberg RA: Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol. 10:251–337. 1994. View Article : Google Scholar : PubMed/NCBI
33	Lin Y, Liu G, Zhang Y, Hu YP, Yu K, Lin C, McKeehan K, Xuan JW, Ornitz DM, Shen MM, et al: Fibroblast growth factor receptor 2 tyrosine kinase is required for prostatic morphogenesis and the acquisition of strict androgen dependency for adult tissue homeostasis. Development. 134:723–734. 2007. View Article : Google Scholar : PubMed/NCBI
34	Moon SM, Kim SA, Yoon JH and Ahn SG: HOXC6 is deregulated in human head and neck squamous cell carcinoma and modulates Bcl-2 expression. J Biol Chem. 287:35678–35688. 2012. View Article : Google Scholar : PubMed/NCBI
35	Cho S, Lu M, He X, Ee PL, Bhat U, Schneider E, Miele L and Beck WT: Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells. Proc Natl Acad Sci USA. 108:20778–20783. 2011. View Article : Google Scholar : PubMed/NCBI
36	Chiu LY, Hu ME, Yang TY, Hsin IL, Ko JL, Tsai KJ and Sheu GT: Immunomodulatory protein from ganoderma microsporum induces pro-death autophagy through Akt-mTOR-p70S6K pathway inhibition in multidrug resistant lung cancer cells. PLoS One. 10:e01257742015. View Article : Google Scholar : PubMed/NCBI
37	Galoian K, Temple HT and Galoyan A: mTORC1 inhibition and ECM-cell adhesion-independent drug resistance via PI3K-AKT and PI3K-RAS-MAPK feedback loops. Tumour Biol. 33:885–890. 2012. View Article : Google Scholar : PubMed/NCBI
38	Ye S, Shen J, Choy E, Yang C, Mankin H, Hornicek F and Duan Z: p53 overexpression increases chemosensitivity in multidrug-resistant osteosarcoma cell lines. Cancer Chemother Pharmacol. 77:349–356. 2016. View Article : Google Scholar
39	Yajima T, Ochiai H, Uchiyama T, Takano N, Shibahara T and Azuma T: Resistance to cytotoxic chemotherapy-induced apoptosis in side population cells of human oral squamous cell carcinoma cell line Ho-1-N-1. Int J Oncol. 35:273–280. 2009.PubMed/NCBI
40	Yan S, Ma D, Ji M, Guo D, Dai J, Zhao P and Ji C: Expression profile of Notch-related genes in multidrug resistant K562/A02 cells compared with parental K562 cells. Int J Lab Hematol. 32:150–158. 2010. View Article : Google Scholar
41	Zhou H, Tang Y, Liang X, Yang X, Yang J, Zhu G, Zheng M and Zhang C: RNAi targeting urokinase-type plasminogen activator receptor inhibits metastasis and progression of oral squamous cell carcinoma in vivo. Int J Cancer. 125:453–462. 2009. View Article : Google Scholar : PubMed/NCBI
42	Yang JM, Xu Z, Wu H, Zhu H, Wu X and Hait WN: Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells. Mol Cancer Res. 1:420–427. 2003.PubMed/NCBI
43	Liu QH, Shi ML, Sun C, Bai J and Zheng JN: Role of the ERK1/2 pathway in tumor chemoresistance and tumor therapy. Bioorg Med Chem Lett. 25:192–197. 2015. View Article : Google Scholar