Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

Abstract

BackgroundCurrent treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment.MethodsThe mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model.ResultsTreatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts.ConclusionsThis proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies.

JAK2/STAT3 pathway as a therapeutic target in ovarian cancers

“…Several studies evaluated inhibition of JAK2/STAT3 pathway in ovarian cancers, and it is suggested that activation of STAT3 was associated with proliferation, chemo-resistance, and cancer stem-cell phenotype (26)(27)(28)(29)(30). So, it was speculated that worse PFS in the patients with positive p-STAT3 tumors was contributed by a high abundance of the patients that showed chemo-resistance of primary tumors, although significance was not obtained (P= 0.055).…”

Janus Kinase 1 Is Essential for Inflammatory Cytokine Signaling and Mammary Gland Remodeling

“…These are two new and important findings because previous studies have suggested that JAK1 and JAK2 are capable of activating STAT3 in response to inflammatory cytokines in diverse cell culture models (reviewed by Kisseleva et al [20]). Although it was recognized nearly 2 decades ago that JAK1 plays a role in IL-6 signaling (21,45,46), more recent work has singled out JAK2 as the master regulator for STAT3 activation in breast cancer and other malignancies (47)(48)(49). This paradigm is likely the result of the fact that pharmacological agents labeled "JAK2 inhibitors" were being utilized in most of the recently published experiments.…”

Inhibition of JAK2 Reverses Paclitaxel Resistance in Human Ovarian Cancer Cells

“…12,18 Recently, STAT3 activation has been implicated in the enrichment of cancer stem cell-like residue population in isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line after paclitaxel treatment. 19 Of note, persistently activated STAT3 promotes tumor cell proliferation, survival, and invasion via promoting pro-oncogenic pathways including nuclear factor-JB and interleukin-6/GP130/JAK2 signaling and by opposing the STAT1 and nuclear factor-JBYmediated T h 1 antitumor immunity. 20 Collectively, STAT3 exerts global impact on ovarian cancer biology, including drug efflux transporters, prosurvival genes, and immune responses in the tumor microenvironment.…”