Curcumin-induced antitumor effects on triple-negative breast cancer patient-derived xenograft tumor mice through inhibiting salt-induced kinase-3 protein

Tzu-Chun Cheng ^a,1, John Oliver Sayseng ^b,1, Shih-Hsin Tu ^c,d,e,1, Ting-Ching Juan ^a, Chia-Lang Fang ^f,g, You-Cheng Liao ^h, Cheng-Ying Chu ^i,j, Hui-Wen Chang ^k, Yun Yen ⁱ, Li-Ching Chen ^i,*, Yuan-Soon Ho ^a,h,i,k,**

a School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan

b International Graduate Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

c Taipei Cancer Center, Taipei Medical University, Taipei 110, Taiwan

d Breast Medical Center, Taipei Medical University Hospital, Taipei 110, Taiwan

e Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

f Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

g Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan

h Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

i TMU Research Center of Cancer Translational Medicine, Taipei Medical University; Taipei 110, Taiwan

j CRISPR Gene Targeting Core Lab, Taipei Medical University, Taipei 110, Taiwan

k Department of Medical Laboratory, Taipei Medical University Hospital, Taipei, Taiwan

This study demonstrated for the first time that curcumin effectively inhibits the growth of triple-negative breast cancer (TNBC) tumors by inhibiting the expression of salt-induced kinase-3 (SIK3) protein in patient-derived xenografted tumor mice (TNBC-PDX). For TNBC patients, chemotherapy is the only option for postoperative adjuvant treatment. In this study, we detected the SIK3 mRNA expression in paired-breast cancer tissues by PCR analysis. The results revealed that SIK3 mRNA expression was significantly higher in tumor tissues when compared to the normal adjacent tissues (73.25 times, n=183). Thus, it is proposed for the first time that the antitumor effect induced by curcumin by targeting SIK3 can be used as a novel strategy for the therapy of TNBC tumors. In vitro mechanism studies have shown that curcumin (>25 μM) inhibits the SIK3-mediated cyclin D upregulation, thereby inhibiting the G1/S cell cycle and arresting TNBC (MDA-MB-231) cancer cell growth. The SIK3 overexpression was associated with increased mesenchymal markers (i.e., Vimentin, α-SMA, MMP3, and Twist) during epithelial-mesenchymal transition (EMT). Our results demonstrated that curcumin inhibits the SIK3-mediated EMT, effectively attenuating the tumor migration. For clinical indications, dietary nutrients (such as curcumin) as an adjuvant to chemotherapy should be helpful to TNBC patients because the current trend is to shrink the tumor with preoperative chemotherapy and then perform surgery. In addition, from the perspective of chemoprevention, curcumin has excellent clinical application value.

Keywords: Curcumin, Epithelial-mesenchymal transition, Patient-derived xenografted mice, Salt-induced kinase-3, Triple-negative breast cancer

https://doi.org/10.38212/2224-6614.3387