HMGB1 Promotes ERK-mediated Mitochondrial Drp1 Phosphorylation for Chemoresistance Through RAGE in Colorectal Cancer

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2018 Sep 28

PMID 30258050

Citations 89

Authors

Shu-Fen Chiang

William Tzu-Liang Chen

Tao-Wei Ke

Tsung-Wei Chen

Ying-Shu You

Chen-Yu Lin

K S Clifford Chao

Chih-Yang Huang

Affiliations

Soon will be listed here.

Abstract

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.

Citing Articles

Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.

Huang D, Li Y, Guo Y, Weng M, Ye H, Zhang Y Commun Biol. 2025; 8(1):338.

PMID: 40021770 PMC: 11871300. DOI: 10.1038/s42003-025-07654-3.

The role of mitochondrial biogenesis, mitochondrial dynamics and mitophagy in gastrointestinal tumors.

Liu Y, Wang H, Zhang S, Peng N, Hai S, Zhao H Cancer Cell Int. 2025; 25(1):46.

PMID: 39955547 PMC: 11829463. DOI: 10.1186/s12935-025-03685-2.

CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function.

Wang Y, Ji Q, Cao N, Ge G, Li X, Liu X Cancer Metab. 2024; 12(1):33.

PMID: 39468645 PMC: 11520061. DOI: 10.1186/s40170-024-00360-4.

Eye on the horizon: The metabolic landscape of the RPE in aging and disease.

Hansman D, Du J, Casson R, Peet D Prog Retin Eye Res. 2024; 104:101306.

PMID: 39433211 PMC: 11833275. DOI: 10.1016/j.preteyeres.2024.101306.

Mitochondria: a new intervention target for tumor invasion and metastasis.

Zhou Q, Cao T, Li F, Zhang M, Li X, Zhao H Mol Med. 2024; 30(1):129.

PMID: 39179991 PMC: 11344364. DOI: 10.1186/s10020-024-00899-4.

References

Taguchi A, Blood D, Del Toro G, Canet A, Lee D, Qu W . Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature. 2000; 405(6784):354-60. DOI: 10.1038/35012626. View

Hofmann M, Drury S, Hudson B, Gleason M, Qu W, Lu Y . RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun. 2002; 3(3):123-35. DOI: 10.1038/sj.gene.6363861. View

Siegel R, Miller K, Fedewa S, Ahnen D, Meester R, Barzi A . Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017; 67(3):177-193. DOI: 10.3322/caac.21395. View

Bhawal U, Ozaki Y, Nishimura M, Sugiyama M, Sasahira T, Nomura Y . Association of expression of receptor for advanced glycation end products and invasive activity of oral squamous cell carcinoma. Oncology. 2005; 69(3):246-55. DOI: 10.1159/000087910. View

Osawa M, Yamamoto Y, Munesue S, Murakami N, Sakurai S, Watanabe T . De-N-glycosylation or G82S mutation of RAGE sensitizes its interaction with advanced glycation endproducts. Biochim Biophys Acta. 2007; 1770(10):1468-74. DOI: 10.1016/j.bbagen.2007.07.003. View

Tanaka A, Youle R . A chemical inhibitor of DRP1 uncouples mitochondrial fission and apoptosis. Mol Cell. 2008; 29(4):409-10. DOI: 10.1016/j.molcel.2008.02.005. View

Xia W, Xu Y, Mao Q, Dong G, Shi R, Wang J . Association of RAGE polymorphisms and cancer risk: a meta-analysis of 27 studies. Med Oncol. 2015; 32(2):442. DOI: 10.1007/s12032-014-0442-5. View

Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K . Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol. 2002; 196(2):163-70. DOI: 10.1002/path.1031. View

Prieto J, Leon M, Ponsoda X, Sendra R, Bort R, Ferrer-Lorente R . Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming. Nat Commun. 2016; 7:11124. PMC: 4821885. DOI: 10.1038/ncomms11124. View

10.

Amornsupak K, Insawang T, Thuwajit P, O-Charoenrat P, Eccles S, Thuwajit C . Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells. BMC Cancer. 2014; 14:955. PMC: 4301465. DOI: 10.1186/1471-2407-14-955. View

11.

Luo Y, Chihara Y, Fujimoto K, Sasahira T, Kuwada M, Fujiwara R . High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy. Eur J Cancer. 2012; 49(3):741-51. DOI: 10.1016/j.ejca.2012.09.016. View

12.

Liu L, Yang M, Kang R, Wang Z, Zhao Y, Yu Y . HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. Leukemia. 2010; 25(1):23-31. DOI: 10.1038/leu.2010.225. View

13.

Zhang R, Li Y, Wang Z, Chen L, Dong X, Nie X . Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis. Tumour Biol. 2015; 36(11):8585-92. DOI: 10.1007/s13277-015-3617-6. View

14.

Tang D, Kang R, Cheh C, Livesey K, Liang X, Schapiro N . HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene. 2010; 29(38):5299-310. PMC: 2945431. DOI: 10.1038/onc.2010.261. View

15.

Lin T, Fan C, Maa M, Leu T . Lipopolysaccharide-promoted proliferation of Caco-2 cells is mediated by c-Src induction and ERK activation. Biomedicine (Taipei). 2015; 5(1):5. PMC: 4331614. DOI: 10.7603/s40681-015-0005-x. View

16.

Huang C, Chiang S, Ke T, Chen T, Lan Y, You Y . Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy. Cancer Immunol Immunother. 2017; 67(4):551-562. PMC: 11028045. DOI: 10.1007/s00262-017-2109-5. View

17.

Rehman J, Zhang H, Toth P, Zhang Y, Marsboom G, Hong Z . Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J. 2012; 26(5):2175-86. PMC: 3336787. DOI: 10.1096/fj.11-196543. View

18.

Amaravadi R, Lippincott-Schwartz J, Yin X, Weiss W, Takebe N, Timmer W . Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011; 17(4):654-66. PMC: 3075808. DOI: 10.1158/1078-0432.CCR-10-2634. View

19.

Huang Q, Zhan L, Cao H, Li J, Lyu Y, Guo X . Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016; 12(6):999-1014. PMC: 4922447. DOI: 10.1080/15548627.2016.1166318. View

20.

Adlard J, Richman S, Seymour M, Quirke P . Prediction of the response of colorectal cancer to systemic therapy. Lancet Oncol. 2002; 3(2):75-82. DOI: 10.1016/s1470-2045(02)00648-4. View