J Cancer Prev.  2021 Sep;26(3):207-217. 10.15430/JCP.2021.26.3.207.

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

• Kim SJ
• Cho NC
• Hahn YI
• Kim SH
• Fang X
• Surh YJ

• KMID: 2521109
• DOI: http://doi.org/10.15430/JCP.2021.26.3.207

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 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.

Keyword

Breast neoplasms; Cyclopentenone prostaglandin; 15-Deoxy-Δ^12,14-prostaglandin J₂; STAT3