STAT3 as an emerging molecular target in pancreatic cancer

Figures & data

Figure 1 Schematic model for the role of STAT3 pathway in various physiological processes.

Notes: After binding to cytokines or growth factor, their receptors get activated and transmit a signal across the cell membrane, which leads to phosphorylation, dimerization, and nuclear translocation of STAT3. This response initiates different cellular and physiological processes. Inflammation results due to differential expression of various cytokines and enzymes such as COX2. Cell survival and proliferation is stimulated by induction of antiapoptotic genes such as Bcl-xl and Bcl-2; upregulation of cyclin B and cyclin D1. Metabolism is affected by altered expression of HSP70, HSP90, and Cdc2. Tumor related functions such as angiogenesis, invasion, and metastasis are triggered by activated STAT3 by regulating the expression of VEGF, FGF, HIF1α, MMP2, MMP9, TWIST, and ICAM1.
Abbreviations: COX2, cyclooxygenase 2; EGF, epidermal growth factor; FGF, fibroblast growth factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; MCP-1, monocyte chemotactic protein-1; P, phosphate; PDGF, platelet-derived growth factor; STAT3, signal transducer and activator of transcription 3; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor.

Table 1 Different agents which directly or indirectly inhibit STAT3 activity in pancreatic cancer cell lines

Treatment	Pancreatic cancer cell lines	Mode of action	Downstream or upstream regulation	Results	References
MicroRNA let-7	BxPC-3, PANC-1, MiaPaCa-2, AsPCI	Suppression of SOCS3	Downregulates VEGF, cyclin D1, and MMP9 genes	Inhibited STAT3 phosphorylation	27
RNA interference	SW1990	STAT3 specific small hairpin RNA to silence STAT3 expression	Downregulates cyclin D1 and Bcl-xL expression	Inhibited cell proliferation, induced cell apoptosis	28
LV-STAT3 small interfering RNA lentivirus vector	SW1990	Lentivirus suppresses expression of STAT3 gene	Decreases VEGF and MMP-2 expression	Inhibited the growth of SW1990 cells and significantly decreased invasion	38
Guggulsterone	CD18/HPAF, Capan 1	Plant polyphenol with known antiproliferative properties	Decreases cyclin Di, Bcl-2, xIAP, MMP9 expression	Inhibited growth and decreased colony formation. Apoptosis and cell cycle arrest Decreased motility and invasion of pancreatic cancer	34
Cucurbitacin B	PANC-1	Plant product with known antiproliferative properties	Upregulates expression of p53 and p2l; downregulates expression of Bcl-2 and survivin	PANC-1 accumulation of G2/M phase cells and apoptosis	37
FLLL31 and FLLL32	PANC-1, BxPC-3, HPAC, SW1990	Binds to JAK2 and the STAT3 SH2 domain	Inhibits STAT3 phosphorylation, DNA binding activity, and transactivation in vitro	Apoptosis, inhibited colony formation and cell invasion FLLL32 inhibited tumor growth and vascularity in chicken embryo xenografts, reduced tumor volumes in mouse	41
Troglitazone and IFN-β	BxPC-3	Troglitazone binds PPAR-γ, which inhibits STAT3	Triggers the autophagy and suppressed beclin-1/Bcl-2 complex; upregulates the expression of p21 and p27	Inhibited growth, with a cell cycle arrest in G0/G1 phase, increase in autophagy	26
EGCG	AsPC-1 and PANC-1	Natural polyphenol of green tea with known antiproliferative properties	Inhibited the expression VEGF, c-Myc, survivin, and cyclin Di	Suppressed growth, invasion, and migration and induced apoptosis	43

Abbreviations: EGCG, epigallocatechin gallate; IFN-β, interferon-β; JAK2, Janus kinase 2; PPAR- γ, peroxisome proliferator-activated receptor-γ; SOS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor.