Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Adenovirus | Primary research

RETRACTED ARTICLE: Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway

Published in: Cancer Cell International | Issue 1/2019

Login to get access

Abstract

Background

5-Fluorouracil (5-FU) is a standard treatment for colorectal cancer, but most patients develop 5-FU resistance. Here, we conducted experiments to identify an effective approach to augment 5-FU-based treatment in colorectal cancer in vitro.

Methods

SW480 cells were in the present study and treated with 5-FU. Besides, LATS2 adenovirus vectors were infected into SW480 cells. Western blotting, immunofluorescence and ELISA were used to evaluate cell death and mitochondrial function. Pathway blocker was used to verify the role of MAPK-JNK pathway in SW480 cell death.

Results

An obvious drop in large tumor suppressor kinase 2 (LATS2) expression was observed in SW480 cells after treatment with 5-FU. In addition, upregulation of LATS2 expression through infection with LATS2 adenovirus further increased the reduction of SW480 cell viability induced by 5-FU. Functional exploration showed that 5-FU treatment suppressed mitochondrial membrane potential, enhanced cyt-c release into the nucleus, induced an oxidative injury environment by promoting ROS production, and eventually upregulated Bax-related mitochondrial apoptosis. Besides, LATS2 overexpression in combination with 5-FU treatment further perturbed mitochondrial homeostasis, and this effect was achieved by elevating mitochondrial division. Mechanistically, LATS2 overexpression and 5-FU co-treatment amplified mitochondrial division by upregulating MIEF1 expression in a manner dependent on MAPK-JNK axis. Knockdown of MIEF1 using an siRNA-mediated loss of function assay and/or inhibition of the MAPK-JNK pathway using the specific inhibitor SP600125 abolished LATS2/5-FU-mediated deleterious effects on mitochondrial performance and SW480 cell viability.

Conclusions

In light of the above findings, LATS2 downregulation could be a potential mechanism of low response to 5-FU treatment. Overexpression of LATS2 to further disrupt mitochondrial function via the JNK-MIEF1 signalling pathway might be a method to optimize 5-FU-based chemotherapy.
Literature
1.
Modest DP, Pant S, Sartore-Bianchi A. Treatment sequencing in metastatic colorectal cancer. Eur J Cancer. 2019;109:70–83.PubMedCrossRef
2.
Olson KR, Gao Y, Arif F, Arora K, Patel S, DeLeon ER, Sutton TR, Feelisch M, Cortese-Krott MM, Straub KD. Metabolism of hydrogen sulfide (H2S) and Production of Reactive Sulfur Species (RSS) by superoxide dismutase. Redox Biol. 2018;15:74–85.PubMedCrossRef
3.
Marjaneh RM, Khazaei M, Ferns GA, Avan A, Aghaee-Bakhtiari SH. The role of microRNAs in 5-FU resistance of colorectal cancer: possible mechanisms. J Cell Physiol. 2019;234(3):2306–16.PubMedCrossRef
4.
Ding X, Sun W, Chen J. IL-2 augments the sorafenib-induced apoptosis in liver cancer by promoting mitochondrial fission and activating the JNK/TAZ pathway. Cancer Cell Int. 2018;18:176.PubMedPubMedCentralCrossRef
5.
6.
Wei R, Cao J, Yao S. Matrine promotes liver cancer cell apoptosis by inhibiting mitophagy and PINK1/Parkin pathways. Cell Stress Chaperones. 2018;23:1295–309.PubMedPubMedCentralCrossRef
7.
Zhou H, Zhu P, Wang J, Zhu H, Ren J, Chen Y. Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2alpha-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death Differ. 2018;25(6):1080–93.PubMedPubMedCentralCrossRef
8.
Huang CY, Chiang SF, Chen WT, Ke TW, Chen TW, You YS, Lin CY, Chao KSC, Huang CY. HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer. Cell Death Dis. 2018;9(10):1004.PubMedPubMedCentralCrossRef
9.
Moore JB, Tang XL, Zhao J, Fischer AG, Wu WJ, Uchida S, Gumpert AM, Stowers H, Wysoczynski M, Bolli R. Epigenetically modified cardiac mesenchymal stromal cells limit myocardial fibrosis and promote functional recovery in a model of chronic ischemic cardiomyopathy. Basic Res Cardiol. 2018;114(1):3.PubMedPubMedCentralCrossRef
10.
Zhao L, Li S, Wang S, Yu N, Liu J. The effect of mitochondrial calcium uniporter on mitochondrial fission in hippocampus cells ischemia/reperfusion injury. Biochem Biophys Res Commun. 2015;461(3):537–42.PubMedCrossRef
11.
Su X, Teng J, Jin G, Li J, Zhao Z, Cao X, Guo Y, Guo M, Li X, Wu J, et al. ELK1-induced upregulation of long non-coding RNA MIR100HG predicts poor prognosis and promotes the progression of osteosarcoma by epigenetically silencing LATS1 and LATS2. Biomed Pharmacother. 2019;109:788–97.PubMedCrossRef
12.
Zhu H, Jin Q, Li Y, Ma Q, Wang J, Li D, Zhou H, Chen Y. Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[Ca(2+)]c/VDAC-[Ca(2+)]m axis by activation of MAPK/ERK signaling pathway. Cell Stress Chaperones. 2018;23(1):101–13.PubMedCrossRef
13.
Sinha B, Wu Q, Li W, Tu Y, Sirianni AC, Chen Y, Jiang J, Zhang X, Chen W, Zhou S et al. Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. J Pineal Res. 2018;64:e12534.CrossRef
14.
Zhou H, Li D, Zhu P, Ma Q, Toan S, Wang J, Hu S, Chen Y, Zhang Y. Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury. J Pineal Res. 2018;65(3):e12503.PubMedCrossRef
15.
16.
Abeysuriya RG, Lockley SW, Robinson PA, Postnova S. A unified model of melatonin, 6-sulfatoxymelatonin, and sleep dynamics. J Pineal Res. 2018;64(4):e12474.PubMedCrossRef
17.
Abukar Y, Ramchandra R, Hood SG, McKinley MJ, Booth LC, Yao ST, May CN. Increased cardiac sympathetic nerve activity in ovine heart failure is reduced by lesion of the area postrema, but not lamina terminalis. Basic Res Cardiol. 2018;113(5):35.PubMedCrossRef
18.
19.
Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, et al. Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol. 2018;113(5):39.PubMedPubMedCentralCrossRef
20.
Boga JA, Caballero B, Potes Y, Perez-Martinez Z, Reiter RJ, Vega-Naredo I, Coto-Montes A. Therapeutic potential of melatonin related to its role as an autophagy regulator: a review. J Pineal Res. 2018;66:e12534.PubMedCrossRef
21.
Fukumoto M, Kondo K, Uni K, Ishiguro T, Hayashi M, Ueda S, Mori I, Niimi K, Tashiro F, Miyazaki S, et al. Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas. Angiogenesis. 2018;21(2):203–14.PubMedCrossRef
22.
Coverstone ED, Bach RG, Chen L, Bierut LJ, Li AY, Lenzini PA, O’Neill HC, Spertus JA, Sucharov CC, Stitzel JA, et al. A novel genetic marker of decreased inflammation and improved survival after acute myocardial infarction. Basic Res Cardiol. 2018;113(5):38.PubMedPubMedCentralCrossRef
23.
Brazao V, Colato RP, Santello FH, Vale GTD, Gonzaga NA, Tirapelli CR, Prado JCD Jr. Effects of melatonin on thymic and oxidative stress dysfunctions during Trypanosoma cruzi infection. J Pineal Res. 2018;65(3):e12510.PubMedCrossRef
24.
Gianni-Barrera R, Butschkau A, Uccelli A, Certelli A, Valente P, Bartolomeo M, Groppa E, Burger MG, Hlushchuk R, Heberer M, et al. PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation. Angiogenesis. 2018;21(4):883–900.PubMedPubMedCentralCrossRef
25.
Davidson SM, Arjun S, Basalay MV, Bell RM, Bromage DI, Botker HE, Carr RD, Cunningham J, Ghosh AK, Heusch G, et al. The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection-evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology. Basic Res Cardiol. 2018;113(6):43.PubMedPubMedCentralCrossRef
26.
Ding M, Ning J, Feng N, Li Z, Liu Z, Wang Y, Wang Y, Li X, Huo C, Jia X, et al. Dynamin-related protein 1-mediated mitochondrial fission contributes to post-traumatic cardiac dysfunction in rats and the protective effect of melatonin. J Pineal Res. 2018;64:e12447.CrossRef
27.
Giatsidis G, Cheng L, Haddad A, Ji K, Succar J, Lancerotto L, Lujan-Hernandez J, Fiorina P, Matsumine H, Orgill DP. Noninvasive induction of angiogenesis in tissues by external suction: sequential optimization for use in reconstructive surgery. Angiogenesis. 2018;21(1):61–78.PubMedCrossRef
28.
DeLeon-Pennell KY, Mouton AJ, Ero OK, Ma Y, Padmanabhan Iyer R, Flynn ER, Espinoza I, Musani SK, Vasan RS, Hall ME, et al. LXR/RXR signaling and neutrophil phenotype following myocardial infarction classify sex differences in remodeling. Basic Res Cardiol. 2018;113(5):40.PubMedPubMedCentralCrossRef
29.
Zhou H, Zhang Y, Hu S, Shi C, Zhu P, Ma Q, Jin Q, Cao F, Tian F, Chen Y. Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis. J Pineal Res. 2017;63:e12413.PubMedPubMedCentralCrossRef
30.
Erland LAE, Shukla MR, Singh AS, Murch SJ, Saxena PK. Melatonin and serotonin: mediators in the symphony of plant morphogenesis. J Pineal Res. 2018;64:e12452.CrossRef
31.
Gonzalez NR, Liou R, Kurth F, Jiang H, Saver J. Antiangiogenesis and medical therapy failure in intracranial atherosclerosis. Angiogenesis. 2018;21(1):23–35.PubMedCrossRef
32.
Deussen A. Mechanisms underlying coronary autoregulation continue to await clarification. Basic Res Cardiol. 2018;113(5):34.PubMedCrossRef
33.
Korbel C, Gerstner MD, Menger MD, Laschke MW. Notch signaling controls sprouting angiogenesis of endometriotic lesions. Angiogenesis. 2018;21(1):37–46.PubMedCrossRef
34.
Edwards KS, Ashraf S, Lomax TM, Wiseman JM, Hall ME, Gava FN, Hall JE, Hosler JP, Harmancey R. Uncoupling protein 3 deficiency impairs myocardial fatty acid oxidation and contractile recovery following ischemia/reperfusion. Basic Res Cardiol. 2018;113(6):47.PubMedPubMedCentralCrossRef
35.
36.
37.
Zhou H, Yue Y, Wang J, Ma Q, Chen Y. Melatonin therapy for diabetic cardiomyopathy: a mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal. 2018;47:88–100.PubMedCrossRef
38.
Jung M, Dodsworth M, Thum T. Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction. Basic Res Cardiol. 2018;114(1):4.PubMedPubMedCentralCrossRef
39.
Fernandez Vazquez G, Reiter RJ, Agil A. Melatonin increases brown adipose tissue mass and function in Zucker diabetic fatty rats: implications for obesity control. J Pineal Res. 2018;64(4):e12472.PubMedCrossRef
40.
Zhou H, Li D, Zhu P, Hu S, Hu N, Ma S, Zhang Y, Han T, Ren J, Cao F, et al. Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARgamma/FUNDC1/mitophagy pathways. J Pineal Res. 2017;63:e12438.CrossRef
41.
42.
Kazakov A, Hall RA, Werner C, Meier T, Trouvain A, Rodionycheva S, Nickel A, Lammert F, Maack C, Bohm M, et al. Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress. Basic Res Cardiol. 2018;113(6):42.PubMedPubMedCentralCrossRef
43.
Wan J, Cui J, Wang L, Wu K, Hong X, Zou Y, Zhao S, Ke H. Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways. Cancer Cell Int. 2018;18:165.PubMedPubMedCentralCrossRef
44.
Zhou H, Wang J, Zhu P, Zhu H, Toan S, Hu S, Ren J, Chen Y. NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2alpha. Basic Res Cardiol. 2018;113(4):23.PubMedCrossRef
45.
Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Bradley MD, Wagner BA, Buettner GR, Monga V, Milhem M, Spitz DR, Allen BG. Redox active metals and H2O2 mediate the increased efficacy of pharmacological ascorbate in combination with gemcitabine or radiation in pre-clinical sarcoma models. Redox Biol. 2018;14:417–22.PubMedCrossRef
46.
Tan SWS, Yip GW, Suda T, Baeg GH. Small Maf functions in the maintenance of germline stem cells in the Drosophila testis. Redox Biol. 2018;15:125–34.PubMedCrossRef
47.
Zhou H, Zhu P, Guo J, Hu N, Wang S, Li D, Hu S, Ren J, Cao F, Chen Y. Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. Redox Biol. 2017;13:498–507.PubMedPubMedCentralCrossRef
48.
Li R, Xin T, Li D, Wang C, Zhu H, Zhou H. Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol. 2018;18:229–43.PubMedPubMedCentralCrossRef
49.
Zhang B, Hou R, Zou Z, Luo T, Zhang Y, Wang L, Wang B. Mechanically induced autophagy is associated with ATP metabolism and cellular viability in osteocytes in vitro. Redox Biol. 2018;14:492–8.PubMedCrossRef
50.
Zhou H, Wang S, Hu S, Chen Y, Ren J. ER-mitochondria microdomains in cardiac ischemia-reperfusion injury: a fresh perspective. Front Physiol. 2018;9:755.PubMedPubMedCentralCrossRef
51.
Zhu P, Hu S, Jin Q, Li D, Tian F, Toan S, Li Y, Zhou H, Chen Y. Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: a mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biol. 2018;16:157–68.PubMedPubMedCentralCrossRef
52.
Shi C, Cai Y, Li Y, Li Y, Hu N, Ma S, Hu S, Zhu P, Wang W, Zhou H. Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biol. 2018;14:59–71.PubMedCrossRef
53.
Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 2018;15:335–46.PubMedCrossRef
54.
Zhou H, Wang J, Hu S, Zhu H, Toanc S, Ren J. BI1 alleviates cardiac microvascular ischemia-reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F-actin pathways. J Cell Physiol. 2019;234(4):5056–69.PubMedCrossRef
55.
Li DJ, Fu H, Tong J, Li YH, Qu LF, Wang P, Shen FM. Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress. Redox Biol. 2018;15:22–33.PubMedCrossRef
56.
Masaldan S, Clatworthy SAS, Gamell C, Meggyesy PM, Rigopoulos AT, Haupt S, Haupt Y, Denoyer D, Adlard PA, Bush AI, et al. Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol. 2018;14:100–15.PubMedCrossRef
57.
Paul S, Gangwar A, Bhargava K, Ahmad Y. STAT3-RXR-Nrf2 activates systemic redox and energy homeostasis upon steep decline in pO2 gradient. Redox Biol. 2018;14:423–38.PubMedCrossRef
58.
Jin Q, Li R, Hu N, Xin T, Zhu P, Hu S, Ma S, Zhu H, Ren J, Zhou H. DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol. 2018;14:576–87.PubMedCrossRef
59.
60.
Kingnate C, Charoenkwan K, Kumfu S, Chattipakorn N, Chattipakorn SC. Possible roles of mitochondrial dynamics and the effects of pharmacological interventions in chemoresistant ovarian cancer. EBioMedicine. 2018;34:256–66.PubMedPubMedCentralCrossRef
61.
Zhou H, Shi C, Hu S, Zhu H, Ren J, Chen Y. BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis. 2018;21(3):599–615.PubMedCrossRef
62.
Li D, Wang X, Huang Q, Li S, Zhou Y, Li Z. Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-kappaB pathway in vivo and in vitro. Redox Biol. 2018;15:62–73.PubMedCrossRef
63.
Yin J, Li Y, Han H, Chen S, Gao J, Liu G, Wu X, Deng J, Yu Q, Huang X, et al. Melatonin reprogramming of gut microbiota improves lipid dysmetabolism in high-fat diet-fed mice. J Pineal Res. 2018;65(4):e12524.PubMedCrossRef
64.
Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J. Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res. 2018;64:e12450.CrossRef
65.
Zhou H, Wang J, Zhu P, Hu S, Ren J. Ripk3 regulates cardiac microvascular reperfusion injury: The role of IP3R-dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration. Cell Signal. 2018;45:12–22.CrossRefPubMedPubMedCentral
66.
Rathore A, Chu Q, Tan D, Martinez TF, Donaldson CJ, Diedrich JK, Yates JR 3rd, Saghatelian A. MIEF1 microprotein regulates mitochondrial translation. Biochemistry. 2018;57(38):5564–75.PubMedCrossRef
Metadata
Title
RETRACTED ARTICLE: Large tumor suppressor kinase 2 overexpression attenuates 5-FU-resistance in colorectal cancer via activating the JNK-MIEF1-mitochondrial division pathway
Publication date
01-12-2019
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0812-3

Other articles of this Issue 1/2019

Cancer Cell International 1/2019 Go to the issue

Review

Resveratrol is a promising agent for colorectal cancer prevention and treatment: focus on molecular mechanisms

Primary research

SLC25A22 promotes proliferation and metastasis by activating MAPK/ERK pathway in gallbladder cancer

Primary research

Novel sulphamoylated 2-methoxy estradiol derivatives inhibit breast cancer migration by disrupting microtubule turnover and organization

Primary research

Low BCL9 expression inhibited ovarian epithelial malignant tumor progression by decreasing proliferation, migration, and increasing apoptosis to cancer cells

Primary research

Low expression of SPARC in gastric cancer-associated fibroblasts leads to stemness transformation and 5-fluorouracil resistance in gastric cancer

Primary research

A 3-circular RNA signature as a noninvasive biomarker for diagnosis of colorectal cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits