J Cancer Prev 2021; 26(3): 207-217
Published online September 30, 2021
© Korean Society of Cancer Prevention
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 2Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon, 3Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, 4Cancer Research Institute, Seoul National University, Seoul, Korea
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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-Δ12,14-prostaglandin J2 (15d-PGJ2) has been well recognized for its capability to modulate intracellular signaling pathways involved in cancer cell growth and progression. We previously reported that 15d-PGJ2 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-PGJ2 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-PGJ2. In contrast, estrogen receptor positive MCF-7 breast cancer cells that do not exhibit elevated STAT3 phosphorylation were much less susceptible to 15d-PGJ2-induced apoptosis as assessed by PARP cleavage. Furthermore, 15d-PGJ2 inhibited interleukin-6-induced tyrosine phosphorylation of STAT3 in LNCaP cells. According to molecular docking studies, 15d-PGJ2 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-PGJ2-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.
Keywords: Breast neoplasms, Cyclopentenone prostaglandin, 15-Deoxy-&Delta,12,14-prostaglandin J2, STAT3
Eun-Ryeong Hahm, Su-Hyeong Kim, Sivapar V. Mathan, Rana P. Singh, Shivendra V. SinghJ Cancer Prev 2021; 26(2): 128-136 https://doi.org/10.15430/JCP.2021.26.2.128
Kyunghwa Cho, Hee Geum Lee, Juan-Yu Piao, Su-Jung Kim, Hye-Kyung Na, Young-Joon SurhJ Cancer Prev 2021; 26(2): 118-127 https://doi.org/10.15430/JCP.2021.26.2.118
Wondimeneh Shibabaw Shiferaw, Yared Asmare Aynalem, Tadesse Yirga Akalu, Tefera Mulugeta DemelewJ Cancer Prev 2020; 25(2): 111-118 https://doi.org/10.15430/JCP.2020.25.2.111