Targeting JAK1/STAT3 Signaling Suppresses Tumor Progression and Metastasis in a Peritoneal Model of Human Ovarian Cancer

Abstract

JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in ovarian cancer patients. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine-cytokine loop involving the IL-6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL-6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL-6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.

Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis

“…Activation of Jak1 has been reported in leukemias, hepatocellular carcinoma, and gynecologic cancers (40–43). In these cases, activation arose through mutation of Jak1, usually within the kinase domain.…”

Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target

“…Although several STAT3 inhibitors suppress tumor growth in preclinical models 36 , thus far none are currently used in the standard treatment of any cancer. Potential reasons for the lack of STAT3 inhibitors in the treatment armamentarium for ovarian cancer include the absence of a clinically relevant model to demonstrate their efficacy 37 as well as difficulties in reaching the target organ 17, 38, 39 . Hence, evaluating novel STAT3 inhibitors using a better orthotopic tumor model, which more closely mimics the clinical presentation of disease and metastatic progression, is essential.…”

“…Cytotoxic anti-cancer agents are notorious for poor bioavailability, low solubility in aqueous solutions, and low potency 23, 41, 42 . While the naturally-occuring curcumin as well as the synthetic small molecule STAT3 inhibitors have shown cytotoxicity in various cancer cells by blocking STAT3 signaling 17, 39, 43, 44 , their clinical implementation has been hindered by relatively low potency and limited cell permeability 41, 42, 45 . In contrast, the oral bioavailability of HO-3867 and selective absorption into tumor tissue represents a substantial advancement in the application of small-molecule STAT3 inhibitors as unique anticancer agents for ovarian cancer.…”

Collagen triple helix repeat containing 1 (CTHRC1) activates Integrin β3/FAK signaling and promotes metastasis in ovarian cancer

“…Briefly, the results from two independent experiments showed a spectrum of proteins whose phosphorylation levels were decreased more than 15% in SKOV3 cells when CTHRC1 was stably knocked down (Table 1). Many of these proteins, when phosphorylated, have been shown to be associated with cell migration, invasion, and tumor metastasis [4, 29–31]. Among these prometestatic proteins, the phosphorylation state of Focal adhesion kinase (FAK) on Tyr397 was dramatically decreased.…”