Effects and mechanisms of AKR1C3 inducing doxorubicin resistance in breast cancer

WANG Kaizhen; YANG Wanwan; XU Shengyao; GUO Qinglong; ZHAO Li

doi:10.11665/j.issn.1000-5048.20210313

Journal of China Pharmaceutical University > 2021 > 52(3): 352-360. > DOI: 10.11665/j.issn.1000-5048.20210313

WANG Kaizhen, YANG Wanwan, XU Shengyao, GUO Qinglong, ZHAO Li. Effects and mechanisms of AKR1C3 inducing doxorubicin resistance in breast cancer[J]. Journal of China Pharmaceutical University, 2021, 52(3): 352-360. DOI: 10.11665/j.issn.1000-5048.20210313

Citation:

PDF (2546 KB)

Effects and mechanisms of AKR1C3 inducing doxorubicin resistance in breast cancer

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

Funds: This study was supported by the National Natural Science Foundation of China (No.81830105)

More Information

Received Date: March 04, 2021
Revised Date: May 12, 2021

Graphical Abstract

Abstract

Abstract

To explore the mechanisms by which AKR1C3 induces tumor resistance, human breast cancer cell strain MCF-7/DOX resistant to doxorubicin, MCF-7/ AKR1C3 cells for overexpression of AKR1C3 and MCF-7/DOX-KD cells for knockdown of AKR1C3 in MCF-7/DOX cells were established. Western blot analysis found that AKR1C3 was expressed at a higher level in MCF-7/DOX than MCF-7 wild type cells. Similarly, CCK-8 and DAPI confirmed that MCF-7/ AKR1C3 cells were more resistant to DOX than AKR1C3 wild types as the IC₅₀ was increased 6 times in MCF-7/AKR1C3 cells more than in AKR1C3 wild type cells. Meanwhile, colony formation ability was also enhanced after AKR1C3 was over-expressed in MCF-7 cells.Cytoplasmic/nuclear separation analysis and IF further found that β-catenin nuclear translocation mediated by AKR1C3 was the main reason contributing to the occurrence of DOX-resistant breast cancer cells. β-catenin inhibitor, XAV939, could reverse the AKR1C3 induced doxorubicin resistance in MCF-7 cells.Results indicated that AKR1C3 could be a potential therapeutic target in breast cancer cells.
- aldo-keto reductase,
- AKR1C3,
- β-catenin,
- breast cancer,
- DOX resistance

FullText(HTML)

References (15)

References

[1]	. CA Cancer J Clin，2019，69（1）：7-34.
[2]	Xu ML，Wang C，Wang N，et al. MALAT1 upregulates SMYD3 by competition with miR-124 and promotes proliferation and migration of breast cancer cells［J］. J China Pharm Univ（中国药科大学学报），2019，50（3）：344-351.
[3]	Greenlee H，Dupont-Reyes MJ，Balneaves LG，et al. Clinical practice guidelines on the evidence-based use of integrative therapies during and after breast cancer treatment［J］. CA Cancer J Clin，2017，67（3）：194-232.
[4]	Howard GR，Johnson KE，Rodriguez Ayala A，et al. A multi-state model of chemoresistance to characterize phenotypic dynamics in breast cancer［J］. Sci Rep，2018，8（1）：12058.
[5]	Bandyopadhyay A，Wang L，Agyin J，et al. Doxorubicin in combination with a small TGFbeta inhibitor：a potential novel therapy for metastatic breast cancer in mouse models［J］. PLoS One，2010，5（4）：e10365.
[6]	Turton NJ，Judah DJ，Riley J，et al. Gene expression and amplification in breast carcinoma cells with intrinsic and acquired doxorubicin resistance［J］. Oncogene，2001，20（11）：1300-1306.
[7]	Penning TM，Burczynski ME，Jez JM，et al. Human 3alpha-hydroxysteroid dehydrogenase isoforms （AKR1C1-AKR1C4） of the aldo-keto reductase superfamily：functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones［J］. Biochem J，2000，351（Pt 1）：67-77.
[8]	Penning TM. AKR1C3 （type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase）：roles in malignancy and endocrine disorders［J］. Mol Cell Endocrinol，2019，489：82-91.
[9]	Liu Y，He SY，Chen Y，et al. Overview of AKR1C3：inhibitor achievements and disease insights［J］. J Med Chem，2020，63（20）：11305-11329.
[10]	Boichuk S，Galembikova A，Sitenkov A，et al. Establishment and characterization of a triple negative basal-like breast cancer cell line with multi-drug resistance［J］. Oncol Lett，2017，14（4）：5039-5045.
[11]	Yamashita N，Kanno Y，Saito N，et al. Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells［J］. Biochem Biophys Res Commun，2019，516（3）：693-698.
[12]	Ruiz de Galarreta M，Bresnahan E，Molina-Sánchez P，et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma［J］. Cancer Discov，2019，9（8）：1124-1141.
[13]	Tenbaum SP，Ordó?ez-Morán P，Puig I，et al. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer［J］. Nat Med，2012，18（6）：892-901.
[14]	Huang SM，Mishina YM，Liu SM，et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling［J］. Nature，2009，461（7264）：614-620.
[15]	Wu C，Yu S，Tan Q，et al. Role of AhR in regulating cancer stem cell-like characteristics in choriocarcinoma［J］. Cell Cycle，2018，17（18）：2309-2320.

Cited By

Get Citation

PDF

XML

Article views (222) PDF downloads (622)

Turn off MathJax

Article Contents

Abstract

References

Effects and mechanisms of AKR1C3 inducing doxorubicin resistance in breast cancer

Abstract

References

Catalog

Export File

Citation

Format

Content