Resistant starch prevents tumorigenesis of dimethylhydrazine-induced colon tumors via regulation of an ER stress-mediated mitochondrial apoptosis pathway

Wang,Qiuyu; Wang,Peng; Xiao,Zhigang

doi:10.3892/ijmm.2018.3423

Resistant starch prevents tumorigenesis of dimethylhydrazine-induced colon tumors via regulation of an ER stress-mediated mitochondrial apoptosis pathway

Authors:
- Qiuyu Wang
- Peng Wang
- Zhigang Xiao
View Affiliations

Affiliations: College of Food Science, Northeast Agricultural University, Harbin, Heilongjiang 150030, P.R. China
Published online on: January 25, 2018 https://doi.org/10.3892/ijmm.2018.3423
Pages: 1887-1898
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Resistant starch is as common soluble fiber that escapes digestion in the small intestine and can regulate intestinal function, metabolism of blood glucose and lipids, and may prevent tumorigenesis of gastrointestinal cancer. Epidemiology and other evidence have suggested that resistant starch may prevent colon cancer development. The aim of the current study was to explore the ameliorative effects and potential mechanisms of resistant starch in the tumorigenesis of colon tumors induced by dimethylhydrazine in C57BL/6 mice. Western blot analysis, ELISA, microscopy, immunofluorescence and immunohistochemistry were used to analyze the efficacy of resistant starch on the metabolic balance in the colon and tumorigenesis of colon tumors. The results demonstrated that a diet containing resistant starch decreased the animal body weight and reduced free ammonia, pH and short chain fatty acids in feces compared with mice that received a standard diet. Resistant starch reduced the incidence of colon tumors and suppressed the expression of carcinogenesis‑associated proteins, including heat shock protein 25, protein kinase C‑d and gastrointestinal glutathione peroxidase in colon epithelial cells compared with standard starch and control groups. Colon tumor cells proliferation and dedifferentiation were significantly decreased by a resistant starch diet. The results also demonstrated that resistant starch increased the apoptosis of colon tumor cells through regulation of apoptosis‑associated gene expression levels in colon tumor cells. Oxidative stress and endoplasmic reticulum stress were upregulated, and elevation eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor‑4 and secretase‑β expression levels were increased in the resistant starch diet group. Additionally, the activity of eIF2α and PERK were increased in colon tumor cells from mice that had received resistant starch. Increasing DNA damage‑inducible transcript 3 protein (CHOP), binding immunoglobulin protein (BIP) and caspase‑12 expression levels upregulated by resistant starch diet may contribute to the resistant starch‑induced apoptosis of colon tumor cells induced by 1,2‑dimethylhydrazine. In vitro assays demonstrated that knockdown of eIF2α inhibited apoptosis of colon tumor cells isolated from mice fed with resistant starch, which also downregulated CHOP, BIP and caspase‑3 expression levels compared with controls. Furthermore, long‑term survival of experimental mice was prolonged by the resistant starch diet compared with the standard diet group. In conclusion, the results indicate that resistant starch in the diet may prevent carcinogenesis of colon epithelial cells, mediated by enhancing apoptosis through an endoplasmic reticulum stress‑mediated mitochondrial apoptosis pathway.

View Figures

View References

1	Lopez NE, Weiss AC, Robles J, Fanta P and Ramamoorthy SL: A systematic review of clinically available gene expression profiling assays for stage II colorectal cancer: Initial steps toward genetic staging. Am J Surg. 212:700–714. 2016. View Article : Google Scholar : PubMed/NCBI
2	Burness CB and Duggan ST: Trifluridine/tipiracil: A review in metastatic colorectal cancer. Drugs. 76:1393–1402. 2016. View Article : Google Scholar : PubMed/NCBI
3	Moriarity A, O'Sullivan J, Kennedy J, Mehigan B and McCormick P: Current targeted therapies in the treatment of advanced colorectal cancer: A review. Ther Adv Med Oncol. 8:276–293. 2016. View Article : Google Scholar : PubMed/NCBI
4	Chibaudel B, Bonnetain F, Tournigand C and de Gramont A: Maintenance treatment in metastatic colorectal cancer. Lancet Oncol. 16:e583–e584. 2015. View Article : Google Scholar : PubMed/NCBI
5	Moilanen JM, Kokkonen N, Löffek S, Väyrynen JP, Syväniemi E, Hurskainen T, Mäkinen M, Klintrup K, Mäkelä J, Sormunen R, et al: Collagen XVII expression correlates with the invasion and metastasis of colorectal cancer. Hum Pathol. 46:434–442. 2015. View Article : Google Scholar : PubMed/NCBI
6	Fan Z, Cui H, Xu X, Lin Z, Zhang X, Kang L, Han B, Meng J, Yan Z, Yan X, et al: MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3. Oncotarget. 6:25266–25280. 2015. View Article : Google Scholar : PubMed/NCBI
7	Zhang XB, Song L, Wen HJ, Bai XX, Li ZJ and Ma LJ: Upregulation of microRNA-31 targeting integrin alpha5 suppresses tumor cell invasion and metastasis by indirectly regulating PI3K/AKT pathway in human gastric cancer SGC7901 cells. Tumour Biol. 37:8317–8325. 2016. View Article : Google Scholar : PubMed/NCBI
8	Guo J, Yu X, Gu J, Lin Z, Zhao G, Xu F, Lu C and Ge D: Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer. Tumour Biol. 37:6371–6378. 2016. View Article : Google Scholar
9	Jiang N, Deng JY, Liu Y, Ke B, Liu HG and Liang H: Incorporation of perineural invasion of gastric carcinoma into the 7th edition tumor-node-metastasis staging system. Tumour Biol. 35:9429–9436. 2014. View Article : Google Scholar : PubMed/NCBI
10	Bukurova IuA, Khankin SL, Krasnov GS, Grigor'eva ES, Mashkova TD, Lisitsin NA, Karpov VL and Beresten' SF: Comparison of 2D analysis and bioinformatics search efficiency for colon cancer marker identification. Mol Biol (Mosk). 44:375–381. 2010.In Russian. View Article : Google Scholar
11	Thompson BA, Goldgar DE, Paterson C, Clendenning M, Walters R, Arnold S, Parsons MT, Michael DW, Gallinger S, Haile RW, et al: Colon Cancer Family Registry: A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: A report from the Colon Cancer Family Registry. Hum Mutat. 34:200–209. 2013. View Article : Google Scholar
12	Ma Z and Boye JI: Research advances on structural characterization of resistant starch and its structure-physiological function relationship: A review. Crit Rev Food Sci Nutr. Sep 19–2016.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI
13	Raigond P, Ezekiel R and Raigond B: Resistant starch in food: A review. J Sci Food Agric. 95:1968–1978. 2015. View Article : Google Scholar
14	Shen D, Bai H, Li Z, Yu Y, Zhang H and Chen L: Positive effects of resistant starch supplementation on bowel function in healthy adults: A systematic review and meta-analysis of randomized controlled trials. Int J Food Sci Nutr. 68:149–157. 2017. View Article : Google Scholar
15	Dronamraju SS, Coxhead JM, Kelly SB, Burn J and Mathers JC: Cell kinetics and gene expression changes in colorectal cancer patients given resistant starch: A randomised controlled trial. Gut. 58:413–420. 2009. View Article : Google Scholar
16	Le Leu RK, Hu Y, Brown IL, Woodman RJ and Young GP: Synbiotic intervention of Bifidobacterium lactis and resistant starch protects against colorectal cancer development in rats. Carcinogenesis. 31:246–251. 2010. View Article : Google Scholar
17	Mathers JC, Movahedi M, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans G, Maher ER, Bertario L, et al: CAPP2 Investigators: Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: An analysis from the CAPP2 randomised controlled trial. Lancet Oncol. 13:1242–1249. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lee JS, Jung WK, Jeong MH, Yoon TR and Kim HK: Sanguinarine induces apoptosis of HT-29 human colon cancer cells via the regulation of Bax/Bcl-2 ratio and caspase-9-dependent pathway. Int J Toxicol. 31:70–77. 2012. View Article : Google Scholar : PubMed/NCBI
19	Crespo I, San-Miguel B, Prause C, Marroni N, Cuevas MJ, González-Gallego J and Tuñón MJ: Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS One. 7:e504072012. View Article : Google Scholar : PubMed/NCBI
20	Wali VB, Bachawal SV and Sylvester PW: Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis. 14:1366–1377. 2009. View Article : Google Scholar : PubMed/NCBI
21	Edagawa M, Kawauchi J, Hirata M, Goshima H, Inoue M, Okamoto T, Murakami A, Maehara Y and Kitajima S: Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through upregulation of death receptor 5 (DR5) by zerumbone and celecoxib. J Biol Chem. 289:21544–21561. 2014. View Article : Google Scholar : PubMed/NCBI
22	Hawkins P, Morton DB, Burman O, Dennison N, Honess P, Jennings M, Lane S, Middleton V, Roughan JV, Wells S, et al: A guide to defining and implementing protocols for the welfare assessment of laboratory animals: eleventh report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement. Lab Anim. 45:1–13. 2011. View Article : Google Scholar
23	Xiao S, Wang J and Xiao N: MicroRNAs as noninvasive biomarkers in bladder cancer detection: a diagnostic meta-analysis based on qRT-PCR data. Int J Biol Markers. 31:e276–e285. 2016. View Article : Google Scholar : PubMed/NCBI
24	Livak and Schmittgen: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCt method. Methods. 25:402–408. 2001. View Article : Google Scholar
25	Atkins C, Liu Q, Minthorn E, Zhang SY, Figueroa DJ, Moss K, Stanley TB, Sanders B, Goetz A, Gaul N, et al: Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 73:1993–2002. 2013. View Article : Google Scholar : PubMed/NCBI
26	Chaveroux C, Carraro V, Canaple L, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Mesclon F, Gatti E, et al: In vivo imaging of the spatiotemporal activity of the eIF2α-ATF4 signaling pathway: Insights into stress and related disorders. Sci Signal. 8:rs52015. View Article : Google Scholar
27	Yuan W, Ahmad S and Najar A: Morin, a plant derived flavonoid, modulates the expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha mediated by AMPK pathway in hepatic stellate cells. Am J Translat Res. 9:5662–5670. 2017.
28	Christova I: Enzyme-linked immunosorbent assay, immunofluorescent assay, and recombinant immunoblotting in the serodiagnosis of early Lyme borreliosis. Int J Immunopathol Pharmacol. 16:261–268. 2003. View Article : Google Scholar : PubMed/NCBI
29	Yamaoka Y, Yamaguchi T, Kinugasa Y, Shiomi A, Kagawa H, Yamakawa Y, Numata M, Sugimoto S, Imai K, Hotta K, et al: Adenocarcinoma arising from jejunal ectopic pancreas mimicking peritoneal metastasis from colon cancer: a case report and literature review. Surg Case Rep. 1:1142015. View Article : Google Scholar :
30	Hirai HW, Tsoi KK, Chan JY, Wong SH, Ching JY, Wong MC, Wu JC, Chan FK, Sung JJ and Ng SC: Systematic review with meta-analysis: Faecal occult blood tests show lower colorectal cancer detection rates in the proximal colon in colonoscopy-verified diagnostic studies. Aliment Pharmacol Ther. 43:755–764. 2016. View Article : Google Scholar : PubMed/NCBI
31	Birt DF and Phillips GJ: Diet, genes, and microbes: Complexities of colon cancer prevention. Toxicol Pathol. 42:182–188. 2014. View Article : Google Scholar :
32	Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, Gaskins HR and O'Keefe SJ: Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 98:111–120. 2013. View Article : Google Scholar : PubMed/NCBI
33	Ridlon JM and Hylemon PB: A potential role for resistant starch fermentation in modulating colonic bacterial metabolism and colon cancer risk. Cancer Biol Ther. 5:273–274. 2006. View Article : Google Scholar : PubMed/NCBI
34	Yueh AE, Payne SN, Leystra AA, Van D Hey DR, Foley TM, Pasch CA, Clipson L, Matkowskyj KA and Deming DA: Colon cancer tumorigenesis initiated by the H1047R mutant PI3K. PLoS One. 11:e01487302016. View Article : Google Scholar : PubMed/NCBI
35	Zhang C, Qu S, Wei X, Feng Y, Zhu H, Deng J, Wang K, Liu K, Liu M, Zhang H, et al: HSP25 downregulation enhanced p53 acetylation by dissociation of SIRT1 from p53 in doxorubicin-induced H9c2 cell apoptosis. Cell Stress Chaperones. 21:251–260. 2016. View Article : Google Scholar
36	Molinari AJ, Pozzi EC, Monti Hughes A, Heber EM, Garabalino MA, Thorp SI, Miller M, Itoiz ME, Aromando RF, Nigg DW, et al: Tumor blood vessel 'normalization' improves the therapeutic efficacy of boron neutron capture therapy (BNCT) in experimental oral cancer. Radiat Res. 177:59–68. 2012. View Article : Google Scholar
37	Marín M, Muskus C, Ramírez JR, Arbelaez LF, Alzate JF and Berberich C: The gene encoding the metacyclogenesis-associated transcript Mat-1 is conserved in the genus Leishmania and shows a tendency to form dimers upon protein expression. Parasitol Res. 86:431–435. 2000. View Article : Google Scholar : PubMed/NCBI
38	Stanton MJ, Dutta S, Zhang H, Polavaram NS, Leontovich AA, Hönscheid P, Sinicrope FA, Tindall DJ, Muders MH and Datta K: Autophagy control by the VEGF-C/NRP-2 axis in cancer and its implication for treatment resistance. Cancer Res. 73:160–171. 2013. View Article : Google Scholar :
39	Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M, Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, et al: Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat Genet. 40:600–608. 2008. View Article : Google Scholar : PubMed/NCBI
40	Hino M, Ichihara H, Matsumoto Y and Ueoka R: Anti-tumor effects of cationic hybrid liposomes against colon carcinoma along with apoptosis in vitro. Biol Pharm Bull. 35:2097–2101. 2012. View Article : Google Scholar : PubMed/NCBI
41	Nabizadeh A, Bamdad T, Arefian E and Razavi Nikoo SH: Autophagy gene activity may act as a key factor for sensitivity of tumor cells to oncolytic vesicular stomatitis virus. Iran J Cancer Prev. 9:e39192016. View Article : Google Scholar : PubMed/NCBI
42	Dagistanli FK, Ozkaya HM, Kucukyoruk B, Biceroglu H, Metin D, Gazioglu N, Oz B, Kadioglu P and Ozturk M: Preoperative somatostatin analogue treatment might trigger apoptosis and autophagy in tumor tissues of patients with acro-megaly: A pilot study. Exp Clin Endocrinol Diabetes:. Jun 20–2016.Epub ahead of print. View Article : Google Scholar
43	Zhai H, Song B, Xu X, Zhu W and Ju J: Inhibition of autophagy and tumor growth in colon cancer by miR-502. Oncogene. 32:1570–1579. 2013. View Article : Google Scholar
44	Jang Y, Park NY, Rostgaard-Hansen AL, Huang J and Jiang Q: Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice. Free Radic Biol Med. 95:190–199. 2016. View Article : Google Scholar : PubMed/NCBI
45	Baskaran R, Poornima P, Priya LB, Huang CY and Padma VV: Neferine prevents autophagy induced by hypoxia through activation of Akt/mTOR pathway and Nrf2 in muscle cells. Biomed Pharmacother. 83:1407–1413. 2016. View Article : Google Scholar : PubMed/NCBI
46	Liu W, Shang G, Yang S, Huang J, Xue X, Lin Y, Zheng Y, Wang X, Wang L, Lin R, et al: Electroacupuncture protects against ischemic stroke by reducing autophagosome formation and inhibiting autophagy through the mTORC1-ULK1 complex-Beclin1 pathway. Int J Mol Med. 37:309–318. 2016. View Article : Google Scholar :
47	Khan I, Paul S, Jakhar R, Bhardwaj M, Han J and Kang SC: Novel quercetin derivative TEF induces ER stress and mitochondria-mediated apoptosis in human colon cancer HCT-116 cells. Biomed Pharmacother. 84:789–799. 2016. View Article : Google Scholar : PubMed/NCBI
48	Ho Y, Li X, Jamison S, Harding HP, McKinnon PJ, Ron D and Lin W: PERK activation promotes medulloblastoma tumorigenesis by attenuating premalignant granule cell precursor apoptosis. Am J Pathol. 186:1939–1951. 2016. View Article : Google Scholar : PubMed/NCBI