High Expression of SIRT1 Associates with the Doxorubicin Resistance of Breast Cancer through the Activation of Akt

Author(s): Xiaoxia Jin, Yingze Wei, Yushan Liu, Yali Chen, Bin Zhao, Jieyu Huang, Haiyan Yu, Chunsun Li*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 1 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Background and Purpose: Although limited by side effects and development of resistance, doxorubicin still represents the most common chemotherapy for breast cancer. Thus, the identification of critical molecules to alleviate doxorubicin resistance is crucial. Here, we provide a molecular rationale for the breast cancer patients potentially benefitting from doxorubicin based on the expression levels of SIRT1, an identified member of longevity genes.

Methods: SIRT1-overexpressed and SIRT1-knockdown breast cancer cells were established to investigate the functions of SIRT1 in regulating doxorubicin resistance both in vitro and in vivo. Cell proliferation was analyzed via CCK8 assay, cell apoptosis was studied by TUNEL analysis. Molecule interaction was analyzed through co-immunoprecipitation and immunofluorescence techniques. Sensibility to doxorubicin was assessed in vivo through the nude mice tumorigenicity experiment.

Results: First, SIRT1 was found higher-expressed in breast cancer doxorubicin-resistant cells MCF-7/ADR than that in the doxorubicin- sensitive cells MCF-7. Moreover, SIRT1-knockdown MCF-7/ADR cells showed higher susceptible to doxorubicin both in vitro and in vivo models, whereas overexpressing of SIRT1 inhibited this phenotype. Accordingly, SIRT1 was found interacted with Akt, consequently promoted the activity of Akt in MCF-7/ADR cells in vitro and positively correlated with the expression of P-Akt in vivo. Reversing the activity of Akt partially downturned the doxorubicin-resistant effects mediated by SIRT1.

Conclusion: This investigation suggested the value of SIRT1 as a biomarker of response to doxorubicin, leading to the development of new tools for the management of breast cancer patients.

Keywords: Breast cancer, doxorubicin resistance, doxorubicin-sensitive, SIRT1, Akt, P-Akt.

DeSantis, C.E.; Ma, J.; Goding Sauer, A.; Newman, L.A.; Jemal, A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J. Clin., 2017, 67(6), 439-448.
[http://dx.doi.org/10.3322/caac.21412] [PMID: 28972651]
Akram, M.; Iqbal, M.; Daniyal, M.; Khan, A.U. Awareness and current knowledge of breast cancer. Biol. Res., 2017, 50(1), 33.
[http://dx.doi.org/10.1186/s40659-017-0140-9] [PMID: 28969709]
Kolahdooz, F.; Jang, S.L.; Corriveau, A.; Gotay, C.; Johnston, N.; Sharma, S. Knowledge, attitudes, and behaviours towards cancer screening in indigenous populations: a systematic review. Lancet Oncol., 2014, 15(11), e504-e516.
[http://dx.doi.org/10.1016/S1470-2045(14)70508-X] [PMID: 25281469]
Liu, M.; Yu, X.; Chen, Z.; Yang, T.; Yang, D.; Liu, Q.; Du, K.; Li, B.; Wang, Z.; Li, S.; Deng, Y.; He, N. Aptamer selection and applications for breast cancer diagnostics and therapy. J. Nanobiotechnology, 2017, 15(1), 81.
[http://dx.doi.org/10.1186/s12951-017-0311-4] [PMID: 29132385]
Zhang, X.H.; Hao, S.; Gao, B.; Tian, W.G.; Jiang, Y.; Zhang, S.; Guo, L.J.; Luo, D.L. A network meta-analysis for toxicity of eight chemotherapy regimens in the treatment of metastatic/advanced breast cancer. Oncotarget, 2016, 7(51), 84533-84543.
[http://dx.doi.org/10.18632/oncotarget.13023] [PMID: 27811367]
Ansari, L.; Shiehzadeh, F.; Taherzadeh, Z.; Nikoofal-Sahlabadi, S.; Momtazi-Borojeni, A.A.; Sahebkar, A.; Eslami, S. The most prevalent side effects of pegylated liposomal doxorubicin monotherapy in women with metastatic breast cancer: a systematic review of clinical trials. Cancer Gene Ther., 2017, 24(5), 189-193.
[http://dx.doi.org/10.1038/cgt.2017.9] [PMID: 28409561]
Shafei, A.; El-Bakly, W.; Sobhy, A.; Wagdy, O.; Reda, A.; Aboelenin, O.; Marzouk, A.; El Habak, K.; Mostafa, R.; Ali, M.A.; Ellithy, M. A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer. Biomed. Pharmacother., 2017, 95, 1209-1218.
[http://dx.doi.org/10.1016/j.biopha.2017.09.059] [PMID: 28931213]
Prados, J.; Melguizo, C.; Ortiz, R.; Vélez, C.; Alvarez, P.J.; Arias, J.L.; Ruíz, M.A.; Gallardo, V.; Aranega, A. Doxorubicin-loaded nanoparticles: new advances in breast cancer therapy. Anticancer. Agents Med. Chem., 2012, 12(9), 1058-1070.
[http://dx.doi.org/10.2174/187152012803529646] [PMID: 22339066]
Guarente, L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev., 2000, 14(9), 1021-1026.
[PMID: 10809662]
Hwang, B.J.; Madabushi, A.; Jin, J.; Lin, S.Y.; Lu, A.L. Histoneprotein deacetylase SIRT1 is an anticancer. Am. J. Cancer Res., 2014, 4, 211-221.
[PMID: 24959376]
Wang, R.H.; Sengupta, K.; Li, C.; Kim, H.S.; Cao, L.; Xiao, C.; Kim, S.; Xu, X.; Zheng, Y.; Chilton, B.; Jia, R.; Zheng, Z.M.; Appella, E.; Wang, X.W.; Ried, T.; Deng, C.X. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell, 2008, 14(4), 312-323.
[http://dx.doi.org/10.1016/j.ccr.2008.09.001] [PMID: 18835033]
Roth, M.; Chen, W.Y. Sorting out functions of sirtuins in cancer. Oncogene, 2014, 33(13), 1609-1620.
[http://dx.doi.org/10.1038/onc.2013.120] [PMID: 23604120]
Wang, R.H.; Zheng, Y.; Kim, H.S.; Xu, X.; Cao, L.; Luhasen, T.; Lee, M.H.; Xiao, C.; Vassilopoulos, A.; Chen, W.; Gardner, K.; Man, Y.G.; Hung, M.C.; Finkel, T.; Deng, C.X. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol. Cell, 2008, 32(1), 11-20.
[http://dx.doi.org/10.1016/j.molcel.2008.09.011] [PMID: 18851829]
Olmos, Y.; Brosens, J.J.; Lam, E.W. Interplay between SIRT proteins and tumour suppressor transcription factors in chemotherapeutic resistance of cancer. Drug Resist. Updat., 2011, 14(1), 35-44.
[http://dx.doi.org/10.1016/j.drup.2010.12.001] [PMID: 21195657]
Choi, H.K.; Cho, K.B.; Phuong, N.T.; Han, C.Y.; Han, H.K.; Hien, T.T.; Choi, H.S.; Kang, K.W. SIRT1-mediated FoxO1 deacetylation is essential for multidrug resistance-associated protein 2 expression in tamoxifen-resistant breast cancer cells. Mol. Pharm., 2013, 10(7), 2517-2527.
[http://dx.doi.org/10.1021/mp400287p] [PMID: 23763570]
Sundaresan, N.R.; Pillai, V.B.; Wolfgeher, D.; Samant, S.; Vasudevan, P.; Parekh, V.; Raghuraman, H.; Cunningham, J.M.; Gupta, M.; Gupta, M.P. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci. Signal., 2011, 4(182), ra46.
[http://dx.doi.org/10.1126/scisignal.2001465] [PMID: 21775285]
Pillai, V.B.; Sundaresan, N.R.; Gupta, M.P. Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging. Circ. Res., 2014, 114(2), 368-378.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.300536] [PMID: 24436432]
Liu, P.; Begley, M.; Michowski, W.; Inuzuka, H.; Ginzberg, M.; Gao, D.; Tsou, P.; Gan, W.; Papa, A.; Kim, B.M.; Wan, L.; Singh, A.; Zhai, B.; Yuan, M.; Wang, Z.; Gygi, S.P.; Lee, T.H.; Lu, K.P.; Toker, A.; Pandolfi, P.P.; Asara, J.M.; Kirschner, M.W.; Sicinski, P.; Cantley, L.; Wei, W. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature, 2014, 508(7497), 541-545.
[http://dx.doi.org/10.1038/nature13079] [PMID: 24670654]
Saini, K.S.; Loi, S.; de Azambuja, E.; Metzger-Filho, O.; Saini, M.L.; Ignatiadis, M.; Dancey, J.E.; Piccart-Gebhart, M.J. Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treat. Rev., 2013, 39(8), 935-946.
[http://dx.doi.org/10.1016/j.ctrv.2013.03.009] [PMID: 23643661]
Jin, X.; Wei, Y.; Xu, F.; Zhao, M.; Dai, K.; Shen, R.; Yang, S.; Zhang, N. SIRT1 promotes formation of breast cancer through modulating Akt activity. J. Cancer, 2018, 9(11), 2012-2023.
[http://dx.doi.org/10.7150/jca.24275] [PMID: 29896286]
Lovitt, C.J.; Shelper, T.B.; Avery, V.M. Evaluation of chemotherapeutics in a three-dimensional breast cancer model. J. Cancer Res. Clin. Oncol., 2015, 141(5), 951-959.
[http://dx.doi.org/10.1007/s00432-015-1950-1] [PMID: 25773123]
Kahlem, P.; Dörken, B.; Schmitt, C.A. Cellular senescence in cancer treatment: friend or foe? J. Clin. Invest., 2004, 113(2), 169-174.
[http://dx.doi.org/10.1172/JCI20784] [PMID: 14722606]
Berns, A. Senescence: a companion in chemotherapy? Cancer Cell, 2002, 1(4), 309-311.
[http://dx.doi.org/10.1016/S1535-6108(02)00063-6] [PMID: 12086843]
Wang, Z.; Chen, W. Emerging roles of SIRT1 in cancer drug resistance. Genes Cancer, 2013, 4(3-4), 82-90.
[http://dx.doi.org/10.1177/1947601912473826] [PMID: 24019998]
Xiong, H.; Ni, Z.; He, J.; Jiang, S.; Li, X.; He, J.; Gong, W.; Zheng, L.; Chen, S.; Li, B.; Zhang, N.; Lyu, X.; Huang, G.; Chen, B.; Zhang, Y.; He, F. LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells. Oncogene, 2017, 36(25), 3528-3540.
[http://dx.doi.org/10.1038/onc.2016.521] [PMID: 28166203]
Chu, F.; Chou, P.M.; Zheng, X.; Mirkin, B.L.; Rebbaa, A. Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res., 2005, 65(22), 10183-10187.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-2002] [PMID: 16288004]
Scheid, M.P.; Woodgett, J.R. PKB/AKT: functional insights from genetic models. Nat. Rev. Mol. Cell Biol., 2001, 2(10), 760-768.
[http://dx.doi.org/10.1038/35096067] [PMID: 11584303]
Cheng, G.Z.; Park, S.; Shu, S.; He, L.; Kong, W.; Zhang, W.; Yuan, Z.; Wang, L.H.; Cheng, J.Q. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr. Cancer Drug Targets, 2008, 8(1), 2-6.
[http://dx.doi.org/10.2174/156800908783497159] [PMID: 18288938]
D’Onofrio, N.; Servillo, L.; Balestrieri, M.L. SIRT1 and SIRT6 signaling pathways in cardiovascular disease protection. Antioxid. Redox Signal., 2018, 28(8), 711-732.
[http://dx.doi.org/10.1089/ars.2017.7178] [PMID: 28661724]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [94 - 102]
Pages: 9
DOI: 10.2174/1871520619666191028100405
Price: $65

Article Metrics

PDF: 16