Abstract
Pancreatic cancer is a deadliest type of malignancy and lacks effective intervention. We here report a potential strategy for treatment of this malignancy by the combination of arsenic trioxide (ATO) and BET bromodomain inhibitor JQ1. These two agents synergistically modulate multistages of autophagy and thus induce apoptosis effectively in pancreatic cancer cells. Our genomic and biochemical data have demonstrated that crosstalks between ER stress and autophagy play crucial roles during ATO-induced apoptosis, in which NRF2 may stand at the crossroad between cell death and survival. This has been further strengthened by our finding that NRF2 depletion renders insensitive cells into sensitive ones in regard to ATO treatment-caused cell death. The knockdown of NRF2 and the addition of JQ1 result in similar molecular/cellular effects in promoting effective ATO-induced apoptosis in cells that are insensitive to ATO treatment alone. Thus, the combination of ATO and JQ1 may represent a new treatment strategy for pancreatic cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The raw data of the microarray data have been deposited in Gene Expression Omnibus under GEO: GES124069.
References
Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363:1049–57.
Allemani C, Šekerija M, Lewis C. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391:S0140673617333263.
Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchezrivera FJ, et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015;21:1163–71.
Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:1039–49.
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Hematol Oncol Clin North Am. 2015;29:595–608.
Ghaneh P, Costello E, Neoptolemos JP. Biology and management of pancreatic cancer. Gut. 2008;56:1134–52.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Annu Rev Pathol. 2011;378:607.
Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9:517.
Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sánchez N, Marchesini M, et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514:628–32.
Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25:717–29.
Rosenfeldt MT, O’Prey J, Morton JP, Nixon C, Mackay G, Mrowinska A, et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013;504:296.
Yang A, Rajeshkumar NV, Wang X, Yabuuchi S, Alexander BM, Chu GC, et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Autophagy. 2014;4:905–13.
Iacobuzio-Donahue CA, Herman JM. Autophagy, p53, and pancreatic cancer. N Engl J Med. 2014;370:1352–3.
Kundu M, Thompson CB. Autophagy: basic principles and relevance to disease. Annu Rev Pathol. 2008;3:427.
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069.
Newman RA, Kondo Y, Yokoyama T, Dixon S, Cartwright C, Chan D, et al. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr Cancer Ther. 2007;6:354.
Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol. 2008;182:685–701.
Ktistakis NT, Tooze SA. Digesting the expanding mechanisms of autophagy. Trends Cell Biol. 2016;26:624–35.
Kroemer G, Jäättelä M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005;5:886.
Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy. 2008;4:151.
Pietrocola F, Izzo V, Niso-Santano M, Vacchelli E, Galluzzi L, Maiuri MC, et al. Regulation of autophagy by stress-responsive transcription factors. Semin Cancer Biol. 2013;23:310–22.
Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93.
Hayashinishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol. 2010;11:1433–7.
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–52.
Tallóczy Z, Jiang W, Leib DA, Scheuner D, Kaufman RJ, Eskelinen EL, et al. Regulation of starvation- and virus-induced autophagy by the eIF2alpha kinase signaling pathway. Proc Natl Acad Sci USA. 2002;99:190–5.
Gewirtz DA. The four faces of autophagy: implications for cancer therapy. Cancer Res. 2014;74:647–51.
Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy. Nat Rev Drug Discov. 2007;6:304.
Langdon CG, Platt JT, Means RE, Iyidogan P, Mamillapalli R, Klein M, et al. Combinatorial screening of pancreatic adenocarcinoma reveals sensitivity to drug combinations including bromodomain inhibitor plus neddylation inhibitor. Mol Cancer Ther. 2017;16:1041–53.
Sakamaki JI, Wilkinson S, Hahn M, Tasdemir N, O’Prey J, Clark W, et al. Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function. Mol Cell. 2017;66:517–532.e519.
Wen X, Klionsky DJ. BRD4 is a newly characterized transcriptional regulator that represses autophagy and lysosomal function. Autophagy. 2017;13:1801–3.
Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y, Kondo S. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene. 2005;24:980–91.
Qian W, Liu J, Jin J, Ni W, XU W. Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk Res. 2007;31:329–39.
Sun H, Ma L, Hu X, Zhang T. Ai-Lin I treated 32 cases of acute promyelocytic leukemia. Chin J Integr Chin West Med. 1992;12:170–1.
Xia Y, Fang H, Zhang J, Du Y. Endoplasmic reticulum stress-mediated apoptosis in imatinib-resistant leukemic K562-r cells triggered by AMN107 combined with arsenic trioxide. Exp Biol Med. 2013;238:932–42.
Du Y, Wang K, Fang H, Li J, Xiao D, Zheng P, et al. Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood. 2006;107:1582–90.
Zhang Y, Du Y, Le W, Wang K, Kieffer N, Zhang J. Redox control of the survival of healthy and diseased cells. Antioxid Redox Signal. 2011;15:2867.
Cho HY, Reddy SPKleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal. 2006;8:76.
Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, et al. Direct interaction between Nrf2 and p21Cip1/WAF1 upregulates the Nrf2-mediated antioxidant response. Mol Cell. 2009;34:663–73.
Denicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475:106–9.
Wang K, Fang H, Xiao D, Zhu X, He M, Pan X, et al. Converting redox signaling to apoptotic activities by stress-responsive regulators HSF1 and NRF2 in Fenretinide treated cancer cells. PloS ONE. 2009;4:e7538.
Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63:173–84.
Shah P, Trinh E, Qiang L, Xie L, Hu WY, Prins GS, et al. Arsenic induces p62 expression to form a positive feedback loop with Nrf2 in human epidermal keratinocytes: implications for preventing arsenic-induced skin cancer. Molecules. 2017;22:E194.
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.
Garcia PL, Miller AL, Kreitzburg KM, Council LN, Gamblin TL, Christein JD, et al. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016;35:833.
Hussong M, Börno ST, Kerick M, Wunderlich A, Franz A, Sültmann H, et al. The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response. Cell Death and Dis. 2014;5:e1195.
Antonucci L, Fagman JB, Kim JY, Todoric J, Gukovsky I, Mackey M, et al. Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress. Proc Natl Acad Sci USA. 2015;112:6166–74.
Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW. When NRF2 talks, who’s listening?. Antioxid Redox Signal. 2010;13:1649–63..
Martina JA, Diab HI, Lishu L, Jeong AL, Patange S, Raben N, et al. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci Signal. 2014;7:ra9.
Martina JA, Diab HI, Brady OA, Puertollano R. TFEB and TFE3 are novel components of the integrated stress response. EMBO J. 2016;35:479–95.
Zhang TD, Zhang PF, Wang SR, Han T, et al. A preliminary clinical observation on 6 cases of leukemia treated with “Ai-Ling” injection. Heilongjiang Med J. 1973;66–7. http://www.cnki.com.cn/Article/CJFDTotal-HJYY197303015.htm.
Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23:23–34.
Piya S, Andreeff M, Borthakur G. Targeting autophagy to overcome chemoresistance in acute myleogenous leukemia. Autophagy. 2016;13:214–5.
Acknowledgements
We thank HF and Yifen Tang (Ruijin Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University), for their supports on many aspects.
Financial support
This study is supported in part by the National Natural Science Foundation (no. 81370655), and by Distinguished Professorship (JZ) from Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Xu, C., Wang, X., Zhou, Y. et al. Synergy between arsenic trioxide and JQ1 on autophagy in pancreatic cancer. Oncogene 38, 7249–7265 (2019). https://doi.org/10.1038/s41388-019-0930-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-019-0930-3
This article is cited by
-
A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer
Cell Death & Disease (2023)
-
The synergistic effect of eucalyptus oil and retinoic acid on human esophagus cancer cell line SK-GT-4
Egyptian Journal of Medical Human Genetics (2022)
-
Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer
Cell Death & Disease (2022)