Docosahexaenoic acid enhances oxaliplatin-induced autophagic cell death via the ER stress/sesn2 pathway in colorectal cancer

Soyeon Jeong, Dae Yeong Kim, Sang Hee Kang, Hye Kyeong Yun, Jung Lim Kim, Bo Ram Kim, Seong Hye Park, Yoo Jin Na, Min Jee Jo, Yoon A. Jeong, Bu Gyeom Kim, Dae Hee Lee, Sang Cheul Oh

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36 Citations (Scopus)

Abstract

Oxaliplatin is an anticancer drug administered to colorectal cancer (CRC) patients in combination with 5-fluorouracil and antibodies (bevacizumab and cetuximab), thereby significantly improving the survival rate of CRC. However, due to various side effects associated with the above treatment strategy, the need for combinatorial therapeutic strategies has emerged. Based on the demand for new combinatorial therapies and the known antitumor effects of the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), we investigated the Oxaliplatin and DHA combination for its effect. Our results indicated that DHA further enhanced Oxaliplatin-induced cell viability and autophagic cell death, in vitro and in vivo. Oxaliplatin and DHA also increased the expression of Sestrin 2 (SESN2) and endoplasmic reticulum (ER) stress related C/EBP homologous protein (CHOP). Additionally, treatment with Oxaliplatin and DHA enhanced the binding of CHOP to the promotor region of SESN2, increasing SESN2 expression. These results suggested that DHA enhanced Oxaliplatin-induced reduction in cell viability and increase in autophagy via activating SESN2 and increasing ER stress. Thus, SESN2 may be an effective preclinical target for CRC treatment.

Original languageEnglish
Article number982
JournalCancers
Volume11
Issue number7
DOIs
Publication statusPublished - 2019 Jul

Bibliographical note

Funding Information:
s1, Figure S1: Other ω3-PUFAs or ω6-PUFAs have no effect with Oxaliplatin, Figure S2: DHA enhances Oxaliplatin-induced autophagy, Figure S3: Combinatorial treatment with DHA and Oxaliplatin reduces viability Figure S3: Combinatorial treatment with DHA and Oxaliplatin reduces viability and results in SESN2-mediated autophagy in PDC cells. Author Contributions: S.J. and D.Y.K. participated in the study design and conception, execution of the experiments, data analysis and interpretation, and manuscript writing. S.H.K. collected and assembled the TCGA data. H.K.Y. helped with the ChIP assay and in vivo experiments. J.L.K. and B.R.K. participated in experiments, data analysis and interpretation, and manuscript writing. S.H.K. collected and assembled the TCGAdata.H.K.Y.helpedwiththeChIPassayandinvivoexperiments.J.L.K.andB.R.K.participatedinthe experiments. D.-H.L. participated in the concept and data interpretation. S.C.O. participated in data interpretation interpretation of data and designing of figures. S.H.P., Y.J.N., and M.J.J. participated in the data analysis and data interpretation. Y.A.J. and B.G.K. participated in the collection and assembly of data and the in vivo Funding: This work was supported by a National Research Foundation (NRF) of Korea grant funded by the Korean government (MSIP) (NRF-2017R1A2B2011684) and (NRF-2017R1D1A1B03030703). Moreover, we thank interpretation and performed supervision ofthe study. All authors have readand approved the final manuscript.

Funding Information:
Funding: This work was supported by a National Research Foundation (NRF) of Korea grant funded by the Korean government (MSIP) (NRF-2017R1A2B2011684) and (NRF-2017R1D1A1B03030703). Moreover, we thank professor Kyu Lim for providing the GFP-LC3 vector, AA, α-LA, EPA. References Acknowledgments: We thank Kyu Lim for providing the GFP-LC3 vector. 1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30. [CrossRef] Conflicts of Interest: [PubMed] Theauthors declare that they have nocompetinginterests. 2. Bendell, J.C.; Bekaii-Saab, T.S.; Cohn, A.L.; Hurwitz, H.I.; Kozloff, M.; Tezcan, H.; Roach, N.; Mun, Y.; Fish, S.; ReferenceFslick, E.D.; et al. Treatment patterns and clinical outcomes in patients with metastatic colorectal cancer initially treated with FOLFOX-bevacizumab or FOLFIRI-bevacizumab: Results from ARIES, a bevacizumab 1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 2018, 68, 7–30, observational cohort study. Oncologist 2012, 17, 1486–1495. [CrossRef] [PubMed] doi:10.3322/caac.21442. 2.Bendell,J.C.;Bekaii-Saab,T.S.; Cohn,A.L.; Hurwitz, H.I.; Kozloff, M.; Tezcan, H.; Roach,N.;Mun,Y.; Fish, S.; Flick, E.D.; et al. Treatment patterns andclinicaloutcomes inpatientswith metastaticcolorectalcancer initially treated withFOLFOX-bevacizumab or FOLFIRI-bevacizumab: Results fromARIES, a bevacizumab observational cohort study.Oncologist 2012, 17, 1486–1495, doi:10.1634/theoncologist.2012-0190. 3. Mehmood, R.K.; Parker, J.; Ahmed,S.; Qasem,E.; Mohammed, A.A.; Zeeshan, M.;Jehangir,E.Review of Cisplatin andOxaliplatin in Current Immunogenic and Monoclonal Antibodies Perspective. World J. Oncol. 2014, 5, 97–108, doi:10.14740/wjon830w.

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© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Autophagic cell death
  • Colon cancer
  • Docosahexaenoic acid
  • Oxaliplatin
  • Sestrin 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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