STAT3 as a Potential Target for Tumor Suppressive Effects of 15-Deoxy-δ^12,14-prostaglandin J₂ in Triple Negative Breast Cancer

Abstract

STAT3 plays a prominent role in proliferation and survival of tumor cells. Thus, STAT3 has been considered to be a prime target for development of anti-cancer therapeutics. The electrophilic cyclopentenone prostaglandin,15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) has been well recognized for its capability to modulate intracellular signaling pathways involved in cancer cell growth and progression. We previously reported that 15d-PGJ 2 had potent cytotoxicity against harvey-ras transformed human mammary epithelial cells through direct interaction with STAT3. In this study, we have attempted to verify the inhibitory effects of 15d-PGJ 2 on STAT3 signaling in human breast tumor cells. The triple negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468 displaying constitutive phosphorylation of STAT3 on the tyrosine 705 (Tyr705) residue, underwent apoptosis upon inhibition of STAT3 by 15d-PGJ 2 . In contrast, estrogen receptor positive MCF-7 breast cancer cells that do not exhibit elevated STAT3 phosphorylation were much less susceptible to 15d-PGJ 2 -induced apoptosis as assessed by PARP cleavage. Furthermore, 15d-PGJ 2 inhibited interleukin-6-induced tyrosine phosphorylation of STAT3 in LNCaP cells. According to molecular docking studies, 15d-PGJ 2 may preferentially bind to the cysteine 259 residue (Cys259) present in the coiled-coil domain of STAT3. Site-directed mutagenesis of STAT3 identified Cys259 to be the critical amino acid for the 15d-PGJ 2 -induced apoptosis as well as epithelial-to-mesenchymal transition. Taken together, these findings suggest STAT3 inactivation through direct chemical modification of its Cys259 as a potential therapeutic approach for treatment of triple negative breast cancer treatment.

Meta-analysis of the intervention effects of taekwondo on metabolic syndrome indicators

“…After screening, a total of 112 studies were included: 1 Chinese, 12 English, and 99 Korean studies. As numerous indicators were retrieved from a single study and one study included two intervention groups ( Kim and Yang, 2017 ), studies containing multiple indicators were combined, resulting in 45 studies (112 effect value), including one Chinese study ( Luo, 2017 ), 6 English studies ( Kim, 2015 ; Jung et al, 2016 ; Roh et al, 2020 ; Baek et al, 2021 ; Kim et al, 2021 ; Lee et al, 2021 ), and 38 Korean studies ( Choi, 2000 ; Han et al, 2007 ; Kang, 2007 ; 2009 ; OH and Kim, 2007 ; Byeon et al, 2008 ; Kim and Kim, 2008 ; Kim Y H, 2009a ; 2010 ; 2016 ; 2021 ; Kim H. T, 2009 ; Park et al, 2009 ; 2010 ; Ryoo et al, 2009 ; Ko, 2010 ; Kwon et al, 2010 ; 2011a ; 2011b ; Lee, 2010 ; 2020 ; Shin, 2010 ; Nam et al, 2012 ; 2013 ; Cho and Jeoung, 2013 ; Jang et al, 2013 ; Cho and Yoon, 2014 ; Jeong et al, 2014 ; Lee and Choi, 2014 ; Kim and Yang, 2017 ; Lee et al, 2017 ; 2018 ; 2020 ; Kim and Lee, 2018 ; Koh et al, 2018 ; Ha et al, 2020 ; Jeong, 2020 ; Lee and Kim, 2021 ). A total of 1079 subjects were included among the studies, including 539 and 540 subjects in the control and intervention groups, respectively.…”

Sugiol Masters Apoptotic Precision to Halt Gastric Cancer Cell Proliferation

“…Persistent activation of STAT3, a member of the STAT family, is frequently observed in various types of human malignancies. This persistent activation of STAT3 is known to play a crucial role in promoting the growth and survival of cancer cells [26,27]. Essentially, STAT3 is a transcription factor that regulates the expression of genes involved in cell proliferation, survival, and immune responses.…”

“…The dysregulated STAT3 signaling pathway has also been implicated in various types of human tumors, including but not limited to breast cancer, lung cancer, colorectal cancer, and prostate cancer. Therefore, targeting this aberrant STAT3 activity holds great potential as a universal therapeutic strategy for treating a wide variety of human malignancies [26,27]. By specifically blocking STAT3 signaling, it may be possible to disrupt the growth-promoting and survival mechanisms employed by cancer cells across different tumor types.…”