A combination of inhibitors of glycolysis, glutaminolysis and de novo fatty acid synthesis decrease the expression of chemokines in human colon cancer cells Corrigendum in /10.3892/ol.2020.11303

Schcolnik‑Cabrera,Alejandro; Dominguez‑Gómez,Guadalupe; Chávez‑Blanco,Alma; Ramírez‑Yautentzi,Marisol; Morales‑Bárcenas,Rocío; Díaz‑Chávez,José; Taja‑Chayeb,Lucía; Dueñas‑González,Alfonso

doi:10.3892/ol.2019.11008

A combination of inhibitors of glycolysis, glutaminolysis and de novo fatty acid synthesis decrease the expression of chemokines in human colon cancer cells

Corrigendum in: /10.3892/ol.2020.11303

Authors:
- Alejandro Schcolnik‑Cabrera
- Guadalupe Dominguez‑Gómez
- Alma Chávez‑Blanco
- Marisol Ramírez‑Yautentzi
- Rocío Morales‑Bárcenas
- José Díaz‑Chávez
- Lucía Taja‑Chayeb
- Alfonso Dueñas‑González
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Affiliations: Basic Research Division, National Cancer Institute, Mexico City 14080, Mexico
Published online on: October 18, 2019 https://doi.org/10.3892/ol.2019.11008
Pages: 6909-6916

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Abstract

Lonidamine, 6‑Diazo‑5‑oxo‑L‑norleucine (DON) and orlistat are well known inhibitors of glycolysis, glutaminolysis and of de novo fatty acid synthesis, respectively. Although their antitumor effects have been explored in detail, the potential inhibition of the malignant metabolic phenotype and its influence on the expression of chemokines and growth factors involved in colon cancer, have not been previously reported to the best of our knowledge. In the present study, dose‑response curves with orlistat, lonidamine or DON were generated from cell viability assays conducted in SW480 colon cancer cells. In addition, the synergistic effect of these compounds was evaluated in SW480 human colon cancer cells. The determination of the doses used for maximum synergistic efficacy led to the exploration of the mRNA levels of the target genes hexokinase‑2 (HK2), glutaminase‑1 (GLS‑1) and fatty acid synthase (FASN) in human SW480 and murine CT26.WT colon cancer cells. The cell viability was evaluated following transfection with small interfering (si)RNA targeting these genes and was assessed with trypan blue. The expression levels of chemokines and growth factors were quantified in the supernatant of SW480 cells with LEGENDplex™. The combination of lonidamine, DON and orlistat resulted in a synergistic cytotoxic effect and induced the transcription of the corresponding gene targets but their corresponding proteins were actually downregulated. The downregulation of the expression levels of HK2, GLS‑1 and FASN following transfection of the cells with the corresponding siRNA sequences decreased their viability. The treatment significantly reduced the expression levels of 9 chemokines [interleukin‑9, C‑X‑C motif chemokine ligand (CXCL) 10, eotaxin, chemokine ligand (CCL) 9, CXCL5, CCL20, CXCL1, CXCL11 and CCCL4] and one growth factor (stem cell factor). These changes were associated with decreased phosphorylated‑nuclear factor κB‑p65. The data demonstrate that lonidamine, DON and orlistat in combination reduce the expression levels of chemokines and growth factors in colon cancer cells. Additional research is required to investigate the exact way by which both tumor and stromal cells regulate the expression levels of chemokines and growth factors.

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1	Pavlova NN and Thompson CB: The emerging hallmarks of cancer metabolism. Cell Metab. 23:27–47. 2016. View Article : Google Scholar : PubMed/NCBI
2	Kalyanaraman B: Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism. Redox Biol. 12:833–842. 2017. View Article : Google Scholar : PubMed/NCBI
3	Schcolnik-Cabrera A, Chavez-Blanco A, Dominguez-Gomez G and Duenas-Gonzalez A: Understanding tumor anabolism and patient catabolism in cancer-associated cachexia. Am J Cancer Res. 7:1107–1135. 2017.PubMed/NCBI
4	Mathupala SP, Ko YH and Pedersen PL: Hexokinase II: Cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene. 25:4777–4786. 2006. View Article : Google Scholar : PubMed/NCBI
5	Wise DR and Thompson CB: Glutamine addiction: A new therapeutic target in cancer. Trends Biochem Sci. 35:427–433. 2010. View Article : Google Scholar : PubMed/NCBI
6	Kridel SJ, Axelrod F, Rozenkrantz N and Smith JW: Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64:2070–2075. 2004. View Article : Google Scholar : PubMed/NCBI
7	Cervantes-Madrid D, Dominguez-Gomez G, Gonzalez-Fierro A, Perez-Cardenas E, Taja-Chayeb L, Trejo-Becerril C and Duenas-Gonzalez A: Feasibility and antitumor efficacy in vivo, of simultaneously targeting glycolysis, glutaminolysis and fatty acid synthesis using lonidamine, 6-diazo-5-oxo-L-norleucine and orlistat in colon cancer. Oncol Lett. 13:1905–1910. 2017. View Article : Google Scholar : PubMed/NCBI
8	Cervantes-Madrid D and Dueñas-González A: Antitumor effects of a drug combination targeting glycolysis, glutaminolysis and de novo synthesis of fatty acids. Oncol Rep. 34:1533–1542. 2015. View Article : Google Scholar : PubMed/NCBI
9	Matthews H, Deakin J, Rajab M, Idris-Usman M and Nirmalan NJ: Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations. PLoS One. 12:e01733032017. View Article : Google Scholar : PubMed/NCBI
10	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
11	Ramamonjisoa N and Ackerstaff E: Characterization of the tumor microenvironment and tumor-stroma interaction by non-invasive preclinical imaging. Front Oncol. 7:32017. View Article : Google Scholar : PubMed/NCBI
12	Tuccitto A, Shahaj E, Vergani E, Ferro S, Huber V, Rodolfo M, Castelli C, Rivoltini L and Vallacchi V: Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy. Virchows Arch. 474:407–420. 2018. View Article : Google Scholar : PubMed/NCBI
13	Wegiel B, Vuerich M, Daneshmandi S and Seth P: Metabolic switch in the tumor microenvironment determines immune responses to anti-cancer therapy. Front Oncol. 8:2842018. View Article : Google Scholar : PubMed/NCBI
14	Erreni M, Bianchi P, Laghi L, Mirolo M, Fabbri M, Locati M, Mantovani A and Allavena P: Expression of chemokines and chemokine receptors in human colon cancer. Methods Enzymol. 460:105–121. 2009. View Article : Google Scholar : PubMed/NCBI
15	Baier PK, Eggstein S, Wolff-Vorbeck G, Baumgartner U and Hopt UT: Chemokines in human colorectal carcinoma. Anticancer Res. 25:3581–3584. 2005.PubMed/NCBI
16	Hoelzinger DB, Dominguez AL, Cohen PA and Gendler SJ: Inhibition of adaptive immunity by IL9 can be disrupted to achieve rapid T-cell sensitization and rejection of progressive tumor challenges. Cancer Res. 74:6845–6855. 2014. View Article : Google Scholar : PubMed/NCBI
17	Zeng YJ, Lai W, Wu H, Liu L, Xu HY, Wang J and Chu ZH: Neuroendocrine-like cells -derived CXCL10 and CXCL11 induce the infiltration of tumor-associated macrophage leading to the poor prognosis of colorectal cancer. Oncotarget. 7:27394–27407. 2016. View Article : Google Scholar : PubMed/NCBI
18	Coburn LA, Horst SN, Chaturvedi R, Brown CT, Allaman MM, Scull BP, Singh K, Piazuelo MB, Chitnavis MV, Hodges ME, et al: High-throughput multi-analyte Luminex profiling implicates eotaxin-1 in ulcerative colitis. PLoS One. 8:e823002013. View Article : Google Scholar : PubMed/NCBI
19	Kitamura T, Fujishita T, Loetscher P, Revesz L, Hashida H, Kizaka-Kondoh S, Aoki M and Taketo MM: Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc Natl Acad Sci USA. 107:13063–13068. 2010. View Article : Google Scholar : PubMed/NCBI
20	Kawamura M, Toiyama Y, Tanaka K, Saigusa S, Okugawa Y, Hiro J, Uchida K, Mohri Y, Inoue Y and Kusunoki M: CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer. Eur J Cancer. 48:2244–2251. 2012. View Article : Google Scholar : PubMed/NCBI
21	Yildirim K, Colak E, Aktimur R, Gun S, Taskin MH, Nigdelioglu A, Aktimur SH, Karagöz F and Ozlem N: Clinical value of CXCL5 for determining of colorectal cancer. Asian Pac J Cancer Prev. 19:2481–2484. 2018.PubMed/NCBI
22	Kapur N, Mir H, Clark Iii CE, Krishnamurti U, Beech DJ, Lillard JW and Singh S: CCR6 expression in colon cancer is associated with advanced disease and supports epithelial-to-mesenchymal transition. Br J Cancer. 114:1343–1351. 2016. View Article : Google Scholar : PubMed/NCBI
23	Hsu YL, Chen YJ, Chang WA, Jian SF, Fan HL, Wang JY and Kuo PL: Interaction between tumor-associated dendritic cells and colon cancer cells contributes to tumor progression via CXCL1. Int J Mol Sci. 19:E24272018. View Article : Google Scholar : PubMed/NCBI
24	Gao YJ, Liu L, Li S, Yuan GF, Li L, Zhu HY and Cao GY: Down-regulation of CXCL11 inhibits colorectal cancer cell growth and epithelial-mesenchymal transition. Onco Targets Ther. 11:7333–7343. 2018. View Article : Google Scholar : PubMed/NCBI
25	De la Fuente Lopez M, Landskron G, Parada D, Dubois-Camacho K, Simian D, Martinez M, Romero D, Roa JC, Chahuán I, Gutiérrez R, et al: The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour Biol. 40:10104283188100592018. View Article : Google Scholar : PubMed/NCBI
26	Al-haidari AA, Syk I, Jirstrom K and Thorlacius H: CCR4 mediates CCL17 (TARC)-induced migration of human colon cancer cells via RhoA/Rho-kinase signaling. Int J Colorectal Dis. 28:1479–1487. 2013. View Article : Google Scholar : PubMed/NCBI
27	Cambien B, Richard-Fiardo P, Karimdjee BF, Martini V, Ferrua B, Pitard B, Schmid-Antomarchi H and Schmid-Alliana A: CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRβ in colorectal carcinoma. PLoS One. 6:e288422011. View Article : Google Scholar : PubMed/NCBI
28	Roblek M, Strutzmann E, Zankl C, Adage T, Heikenwalder M, Atlic A, Weis R, Kungl A and Borsig L: Targeting of CCL2-CCR2-glycosaminoglycan axis using a CCL2 decoy protein attenuates metastasis through inhibition of tumor cell seeding. Neoplasia. 18:49–59. 2016. View Article : Google Scholar : PubMed/NCBI
29	Tanabe Y, Sasaki S, Mukaida N and Baba T: Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancer-associated fibroblast accumulation. Oncotarget. 7:48335–48345. 2016. View Article : Google Scholar : PubMed/NCBI
30	Bellone G, Carbone A, Sibona N, Bosco O, Tibaudi D, Smirne C, Martone T, Gramigni C, Camandona M, Emanuelli G and Rodeck U: Aberrant activation of c-kit protects colon carcinoma cells against apoptosis and enhances their invasive potential. Cancer Res. 61:2200–2206. 2001.PubMed/NCBI
31	Fatrai S, van Schelven SJ, Ubink I, Govaert KM, Raats D, Koster J, Verheem A, Borel Rinkes IH and Kranenburg O: Maintenance of clonogenic KIT(+) human colon tumor cells requires secretion of stem cell factor by differentiated tumor cells. Gastroenterology. 149:692–704. 2015. View Article : Google Scholar : PubMed/NCBI
32	Ghosh S and Karin M: Missing pieces in the NF-kappaB puzzle. Cell. 109 (Suppl):S81–S96. 2002. View Article : Google Scholar : PubMed/NCBI
33	Del Prete A, Allavena P, Santoro G, Fumarulo R, Corsi MM and Mantovani A: Molecular pathways in cancer-related inflammation. Biochem Med (Zagreb). 21:264–275. 2011. View Article : Google Scholar : PubMed/NCBI