Abstract
Here we sought to determine the relationship between STAT3 activity and Galectin‐3 (Gal‐3) and to investigate the cytotoxic effect of PectaSol‐C Modified Citrus Pectin (Pect‐MCP) as a specific competitive inhibitor of Galectin‐3 (Gal‐3) in combination with Paclitaxel (PTX) to kill the ovarian cancer cell SKOV‐3 multicellular tumor spheroid (MCTS). To this order, SKOV‐3 cells in 2D and 3D cultures were treated with exogenous Gal‐3 for the assessment of STAT3 activity. Two‐way ANOVA main effect and IC50 of each drug Paclitaxel (PTX) and Pect‐MCP or in combination were obtained from MTT assay results. The phosphorylated STAT3 levels, migration, invasion, integrin mRNA and p‐AKTser473 levels were assessed in the absence or presence of each drug alone or in combination. Gal‐3 expression levels were assessed in human serous ovarian cancer (SOC) specimens and its correlation with different integrin mRNA levels was further assessed. Our results showed that Gal‐3 expression level was significantly increased in MCTS compared to monolayer SKOV‐3 cells which triggered STAT3 phosphorylation. Moreover, Pect‐MCP synergized with PTX to kill SKOV3 MCTS through abrogation of STAT3 activity and reduced expression of its downstream target HIF‐1α, reduced integrin mRNA levels, and subsequently decreased AKT activity. There were higher expression levels of Gal‐3 in human high‐grade SOC specimens compared to the normal ovary and borderline SOC which positively and significantly correlated with α5, β2 and β6 integrin mRNA levels. Together, these results revealed for the first time that Pect‐MCP could be considered as a potential drug to enhance the PTX effect on ovarian cancer cells MCTS through inhibition of STAT3 activity.
Highlights
Ovarian cancer (OC) cells are disseminated throughout the abdominal cavity by peritoneal fluid or ascites and often form multilayer spheroid‐like structures which could attach to mesothelium, invade the peritoneum and initiate the metastatic tumor growth.[1,2] These spheroids in ascites are capable of tumorigenesis in vivo and are chemoresistant in vitro.[3,4]Galectin‐3 (Gal‐3) is a unique member of galectin family containing a C‐terminal carbohydrate recognition domain, which binds to β‐galactosides and its N‐terminal domain is needed for Gal‐3 enigmatic behavior and cross‐linking activity.[5]
3.1 | SKOV‐3 multicellular tumor spheroid (MCTS) express higher Gal‐3 expression level compared to monolayer which is associated with increased MCTS viability, survival, and growth
Integrins are involved in the various biological processes which are required for cancer initiation and progression such as cell proliferation and survival, cell adhesion, migration, and invasion.[29]
Summary
Ovarian cancer (OC) cells are disseminated throughout the abdominal cavity by peritoneal fluid or ascites and often form multilayer spheroid‐like structures which could attach to mesothelium, invade the peritoneum and initiate the metastatic tumor growth.[1,2] These spheroids in ascites are capable of tumorigenesis in vivo and are chemoresistant in vitro.[3,4]. Signal transducer and activator of transcription 3 (STAT3) are transiently activated in response to specific growth factors and cytokines, while STAT3 is constitutively activated in many cancerous cells, including OC cells.[10,11] STAT3 activation is responsible for several key factors in tumor progression, involving uncontrolled cell proliferation, angiogenesis promotion and importantly facilitating chemoresistance.[12] In most of the high‐grade serous OC, activated STAT3 (p‐STAT3 tyr705) was localized in the nucleus and was associated with increased chemoresistance and subsequent decreased patient survival.[13] In addition, the sustained activation of the STAT3 pathway was demonstrated in cisplatin‐or paclitaxel‐treated OC cell lines.[14]. We further explored a possible synergistic effect of Pect‐MCP as a specific Gal‐3 competitive inhibitor in combination with PTX to kill ovarian cancer cell MCTS
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