Role of phloretin as a sensitizer to TRAIL‑induced apoptosis in colon cancer

Kim,Jung-Lim; Kim,Jung-Lim; Lee,Dae-Hee; Lee,Dae-Hee; Pan,Cheol-Ho; Pan,Cheol-Ho; Park,Su Jin; Park,Su Jin; Oh,Sang-Cheul; Oh,Sang-Cheul; Lee,Suk-Young; Lee,Suk-Young

doi:10.3892/ol.2022.13441

Role of phloretin as a sensitizer to TRAIL‑induced apoptosis in colon cancer

Authors:
- Jung-Lim Kim
- Dae-Hee Lee
- Cheol-Ho Pan
- Su Jin Park
- Sang-Cheul Oh
- Suk-Young Lee
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Affiliations: Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, Seoul 08308, Republic of Korea, Department of Marine Food Science and Technology, Gangneung‑Wonju National University, Gangneung, Gangwon 25457, Republic of Korea, Natural Product Informatics Research Center, Korea Institute of Science and Technology Gangneung Institute of Natural Products, Gangneung, Gangwon 25451, Republic of Korea, Department of Surgery, Wonkwang University Sanbon Hospital, Gunpo, Gyeonggi 15865, Republic of Korea, Division of Hemato‑Oncology, Department of Internal Medicine, School of Medicine, Wonkwang University Sanbon Hospital, Gunpo, Gyeonggi 15865, Republic of Korea
Published online on: July 19, 2022 https://doi.org/10.3892/ol.2022.13441
Article Number: 321
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Phloretin is one of the apple polyphenols with anticancer activities. Since tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) serves important roles in inducing apoptosis, the present study examined the effect of phloretin on TRAIL‑induced apoptosis in colon cancer cells. Treatment with both phloretin and TRAIL markedly suppressed the survival of cancer cells from several colon cancer cell lines compared with that of cells treated with either TRAIL or phloretin. Additionally, decreased numbers of colonies were observed following addition of phloretin and TRAIL. Furthermore, TRAIL‑ and phloretin‑treated HT‑29‑Luc cells exhibited decreased luciferase activity. Increased apoptosis was observed in phloretin‑ and TRAIL‑treated HT‑29‑Luc colon cancer cells, accompanying elevated levels of cleaved poly(ADP‑ribose) polymerase, and caspase‑3, ‑8 and ‑9. The expression levels of MCL1 apoptosis regulator BCL2 family member (Mcl‑1) were decreased following addition of phloretin in colon cancer cells. In addition, overexpression of Mcl‑1 in phloretin‑ and TRAIL‑treated HT‑29‑Luc cells resulted in increased cell survival. Treatment of HT‑29‑Luc cells with a combination of cycloheximide (CHX) and phloretin led to a more prominent decrease in Mcl‑1 expression compared with that in cells treated with CHX alone, while Mcl‑1 expression was recovered by treatment with MG132. Binding of ubiquitin with Mcl‑1 was verified using immunoprecipitation. Intraperitoneal injection of both TRAIL and phloretin into tumor xenografts was associated with a decreased tumor volume compared with that following injection with either TRAIL or phloretin. Overall, the present results suggest a synergistic effect of phloretin on TRAIL‑induced apoptosis in colon cancer cells.

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1	Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A and Bray F: Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 144:1941–1953. 2019. View Article : Google Scholar : PubMed/NCBI
2	Yang Q, Han L, Li J, Xu H, Liu X, Wang X, Pan C, Lei C, Chen H and Lan X: Activation of Nrf2 by phloretin attenuates palmitic acid-induced endothelial cell oxidative stress via AMPK-dependent signaling. J Agric Food Chem. 67:120–131. 2019. View Article : Google Scholar : PubMed/NCBI
3	Wang G, Gao Y, Wang H, Wang J and Niu X: Phloretin reduces cell injury and inflammation mediated by staphylococcus aureus via targeting sortase B and the molecular mechanism. Appl Microbiol Biotechnol. 102:10665–10674. 2018. View Article : Google Scholar
4	Xu M, Gu W, Shen Z and Wang F: Anticancer activity of phloretin against human gastric cancer cell lines involves apoptosis, cell cycle arrest, and inhibition of cell invasion and JNK signalling pathway. Med Sci Monit. 24:6551–6558. 2018. View Article : Google Scholar
5	Kim U, Kim CY, Lee JM, Oh H, Ryu B, Kim J and Park JH: Phloretin inhibits the human prostate cancer cells through the generation of reactive oxygen species. Pathol Oncol Res. 26:977–984. 2020. View Article : Google Scholar : PubMed/NCBI
6	Hsiao YH, Hsieh MJ, Yang SF, Chen SP, Tsai WC and Chen PN: Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells. Phytomedicine. 62:1529642019. View Article : Google Scholar : PubMed/NCBI
7	Lin ST, Tu SH, Yang PS, Hsu SP, Lee WH, Ho CT, Wu CH, Lai YH, Chen MY and Chen LC: Apple polyphenol phloretin inhibits colorectal cancer cell growth via inhibition of the type 2 glucose transporter and activation of p53-mediated signaling. J Agric Food Chem. 64:6826–6837. 2016. View Article : Google Scholar : PubMed/NCBI
8	Park SY, Kim EJ, Shin HK, Kwon DY, Kim MS, Surh YJ and Park JH: Induction of apoptosis in HT-29 colon cancer cells by phloretin. J Med Food. 10:581–586. 2007. View Article : Google Scholar : PubMed/NCBI
9	von Karstedt S, Montinaro A and Walczak H: Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat Rev Cancer. 17:352–366. 2017. View Article : Google Scholar : PubMed/NCBI
10	Adams JM and Cory S: The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 26:1324–1337. 2007. View Article : Google Scholar : PubMed/NCBI
11	Sedger LM, Glaccum MB, Schuh JC, Kanaly ST, Williamson E, Kayagaki N, Yun T, Smolak P, Le T, Goodwin R and Gliniak B: Characterization of the in vivo function of TNF-alpha-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice. Eur J Immunol. 32:2246–2254. 2002. View Article : Google Scholar
12	Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ and Smyth MJ: Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol. 168:1356–1361. 2002. View Article : Google Scholar
13	Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H and Okumura K: Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med. 195:161–169. 2002. View Article : Google Scholar : PubMed/NCBI
14	Gong H, Cheng W and Wang Y: Tumor necrosis factor-related apoptosis-inducing ligand inhibits the growth and aggressiveness of colon carcinoma via the exogenous apoptosis signaling pathway. Exp Ther Med. 17:41–50. 2019.PubMed/NCBI
15	Ivanov VN, Bhoumik A and Ronai Z: Death receptors and melanoma resistance to apoptosis. Oncogene. 22:3152–3161. 2003. View Article : Google Scholar : PubMed/NCBI
16	Zhang XD, Franco A, Myers K, Gray C, Nguyen T and Hersey P: Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma. Cancer Res. 59:2747–2753. 1999.PubMed/NCBI
17	Abe K, Kurakin A, Mohseni-Maybodi M, Kay B and Khosravi-Far R: The complexity of TNF-related apoptosis-inducing ligand. Ann N Y Acad Sci. 926:52–63. 2000. View Article : Google Scholar
18	Kim JL, Park SH, Jeong S, Kim BR, Na YJ, Jo MJ, Jeong YA, Yun HK, Kim DY, Kim BG, et al: Sea cucumber (Stichopus japonicas) F2 enhanced TRAIL-induced apoptosis via XIAP ubiquitination and ER stress in colorectal cancer cells. Nutrients. 11:10612019. View Article : Google Scholar
19	Kim B, Seo JH, Lee KY and Park B: Icariin sensitizes human colon cancer cells to TRAIL-induced apoptosis via ERK-mediated upregulation of death receptors. Int J Oncol. 56:821–834. 2020.
20	Mahalingam D, Carew JS, Espitia CM, Cool RH, Giles FJ, de Jong S and Nawrocki ST: Heightened JNK activation and reduced XIAP levels promote TRAIL and sunitinib-mediated apoptosis in colon cancer models. Cancers (Basel). 11:8952019. View Article : Google Scholar
21	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 : PubMed/NCBI
22	Choi BY: Biochemical basis of anti-cancer-effects of phloretin-a natural dihydrochalcone. Molecules. 24:2782019. View Article : Google Scholar
23	Wu C: Systemic therapy for colon cancer. Surg Oncol Clin N Am. 27:235–242. 2018. View Article : Google Scholar : PubMed/NCBI
24	Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, et al: Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 5:157–163. 1999. View Article : Google Scholar : PubMed/NCBI
25	Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, et al: Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 104:155–162. 1999. View Article : Google Scholar
26	Lemke J, von Karstedt S, Zinngrebe J and Walczak H: Getting TRAIL back on track for cancer therapy. Cell Death Differ. 21:1350–1364. 2014. View Article : Google Scholar : PubMed/NCBI
27	Surapally S, Jayaprakasam M and Verma RS: Curcumin augments therapeutic efficacy of TRAIL-based immunotoxins in leukemia. Pharmacol Rep. 72:1032–1046. 2020. View Article : Google Scholar : PubMed/NCBI
28	Cao X, Fang L, Gibbs S, Huang Y, Dai Z, Wen P, Zheng X, Sadee W and Sun D: Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother Pharmacol. 59:495–505. 2007. View Article : Google Scholar