PKIB Inhibits Autophagy to Regulate Tamoxifen Resistance in Breast Cancer with Estrogen Receptor-Positive Status

作者全名："Sun, Lu; Zong, Beige; Li, Fei; Qiao, Yina; Jin, Ting; Wang, Yihua; Zhang, Yingzi; Jin, Yudi; Qu, Fanli; Liu, Shengchun"

作者地址："[Sun, Lu; Wang, Yihua; Zhang, Yingzi; Jin, Yudi; Liu, Shengchun] Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400042, Peoples R China; [Sun, Lu; Jin, Ting] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China; [Zong, Beige] Chongqing Univ, Cent Hosp, Chongqing Emergency Med Ctr, Sch Med,Dept Gen Surg, Chongqing 400038, Peoples R China; [Li, Fei] Nankai Univ, State Key Lab Med Chem Biol, Tianjin 300350, Peoples R China; [Li, Fei] Nankai Univ, Coll Pharm, Tianjin 300350, Peoples R China; [Qiao, Yina] German Canc Res Ctr, Div Funct Genome Anal, D-69120 Heidelberg, Germany; [Qu, Fanli] Chongqing Univ, Dept Breast Canc Ctr, Canc Hosp, Chongqing 400000, Peoples R China"

通信作者："Liu, SC (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Endocrine & Breast Surg, Chongqing 400042, Peoples R China."

来源：JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001113065100001

JCR分区：Q4

影响因子：0.8

年份：2023

卷号：37

期号：11

开始页：6217

结束页：6229

文献类型：Article

关键词：PKIB; autophagy; breast cancer; tamoxifen resistance; ATG7

摘要："Background: Tamoxifen is an adjuvant endocrine drug used as first-line therapy for treating breast cancer (BC) with positive estrogen receptor (ER) status. However, its effectiveness is limited by the emergence of tamoxifen resistance (TR) caused by changes in autophagy. The aim of this research was to evaluate the role of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase inhibitor-beta (PKIB) in the emergence of TR in BC, together with its involvement in autophagy. Methods: PKIB expression was assessed in tamoxifen-sensitive and -resistant BC cell lines and clinical specimens using RTqPCR, Western blotting, and immunohistochemistry. Overexpression and knockdown of PKIB were employed to evaluate the effects on autophagy and on the response to tamoxifen in vitro. In addition, the mechanism of PKIB-mediated TR was explored using immunofluorescence and Western blot analysis. Furthermore, the activation of cAMP-responsive element-binding protein (CREB)/Autophagy related gene 7 (ATG7) signaling after knockdown of PKIB was evaluated in MCF7 and T47D cells. Results: PKIB was found to be upregulated in tamoxifen-sensitive cell lines (MCF7 and T47D) and in primary tumor tissues. Knockdown of PKIB promoted TR, both in vivo and in vitro, and markedly increased autophagy levels in tamoxifen-sensitive cells. In contrast, the overexpression of PKIB suppressed autophagy and restored tamoxifen sensitivity in TR cells. Furthermore, the protein levels of ATG7 and pCREB were upregulated in MCF7/si2-PKIB and T47D/si2-PKIB cells. Lastly, Kaplan-Meier survival analysis showed that upregulation of PKIB was associated with favourable prognosis of BC patients. Conclusions: This study demonstrated that PKIB inhibits autophagy via the CREB/ATG7 axis, thereby leading to TR in BC."

基金机构：National Natural Science Foundation of China [81772979]; Chongqing Graduate Research and Innovation Project of the Chongqing Education Committee [CYB18153]; Outstanding Postgraduate Fund of Chongqing Medical University

基金资助正文："The present study was supported by the National Natural Science Foundation of China (grant no. 81772979) , and also supported in part by Chongqing Graduate Research and Innovation Project of the Chongqing Education Committee (2018) (CYB18153) and the outstanding Postgraduate Fund of Chongqing Medical University (2018) for Lu Sun."