The Curcumin Analogs 2-Pyridyl Cyclohexanone Induce Apoptosis via Inhibition of the JAK2–STAT3 Pathway in Human Esophageal Squamous Cell Carcinoma Cells

Abstract

Multiple modifications to the structure of curcumin have been investigated with an aim to improve its potency and biochemical properties. Previously, we have synthesized a series of curcumin analogs. In the present study, the anticancer effect of 2-pyridyl cyclohexanone, one of the curcumin analogs, on esophageal carcinoma Eca109 and EC9706 cell lines and its molecular mechanisms were investigated. 2-Pyridyl cyclohexanone inhibited the proliferation of Eca109 and EC9706 cells by inducing apoptosis as indicated by morphological changes, membrane phospholipid phosphatidylserine ectropion, caspase 3 activation, and cleavage of poly(ADP-ribose) polymerase. Mechanistic studies indicated that 2-pyridyl cyclohexanone disrupted mitochondrial membrane potential, disturbed the balance of the Bcl-2 family proteins, and triggered apoptosis via the mitochondria-mediated intrinsic pathway. In 2-pyridine cyclohexanone-treated cells, the phosphorylation levels of JAK2 and STAT3 were dose-dependently decreased and p38 and p-ERK signals were notably activated in a dose-dependent manner. Moreover, we found that the addition of S3I-201, a STAT3 inhibitor, led to a decreased expression level of Bcl-2 in Eca109 cells. The chromatin immunoprecipitation assay demonstrated that STAT3 bound to the promoter of Bcl-2 in the Eca109 cells. Furthermore, the mutation of four STAT3 binding sites (−1733/−1723, −1627/−1617, −807/−797, and −134/−124) on the promote of Bcl-2 gene alone attenuated the transcriptional activation of STAT3. In addition, down-regulation of STAT3 resulted in less of transcriptional activity of STAT3 on Bcl-2 expression. These data provide a potential molecular mechanism of the apoptotic induction function of 2-pyridyl cyclohexanone, and emphasize its important roles as a therapeutic agent for esophageal squamous carcinoma.

Modulation of aryl hydrocarbon receptor inhibits esophageal squamous cell carcinoma progression by repressing COX2/PGE2/STAT3 axis

“…A significant decrease in PGE2 was in agreement with decreased COX2 expression. *, P < 0.05; **, P < 0.01; ***, P < 0.001; N.S, no significance researches (Liu et al 2018;Wang et al 2018). Modulation of AHR by DIM via repressing the COX2/PGE 2 /STAT3 axis both in vitro and in vivo synergistically inhibited the ESCC growth, progression and metastasis.…”

Crucial role of reactive oxygen species (ROS) for the proapoptotic effects of indirubin derivative DKP‐073 in melanoma cells

“…Of note, specific ERK and AKT inhibitors potentiated the proapoptotic effects of linalool, pointing AKT and ERK activation as pro‐survival mechanisms that may be activated for keeping the celĺs balance between apoptosis induction and viability . Also the curcumin analog, 2‐pyridyl cyclohexanone, induced apoptosis in esophageal squamous carcinoma cell lines via inhibition of STAT3 while pERK was activated . In contrast, other proapoptotic drugs inhibited STAT3 and MEK/ERK in parallel, as reported in B16 melanoma cells for silibinin, a natural polyphenolic flavonoid …”

The Therapeutic and Preventive Efficacy of Curcumin and Its Derivatives in Esophageal Cancer

“…Further treatment with 2-pyridyl cyclohexanone decreased mitochondrial membrane potential in the Eca109 and EC9706 cells and induces apoptosis by suppressing Bcl-2 and Bcl-xL expression, whereas promoted Bid/Bax expression in a dose dependent manner. In conclusion, curcumin analog 2-pyridyl cyclohexanone decreases basal STAT3 phosphorylation and promotes apoptosis of ESCC cells (Wang et al, 2018).…”