ABSTRACT
In breast cancers, the large conductance Ca2+ and voltage sensitive K+ (BKCa) channels have been hypothesized to function as oncoproteins, yet it remains unclear how inhibition of channel activity impacts oncogenesis. We demonstrated herein that iberiotoxin (IbTX), an inhibitor of BKCa channels, differentially modulated the in vitro tumorigenic activities of hormone-independent breast cancer cells. Specifically, in HER-2/neu-overexpressing UACC893 cells and triplenegative MDA-MB-231 cells, IbTX selectively attenuated anchorage-independent growth with concomitant downregulation of ß-catenin as well as total and phosphorylated Akt and HER-2/neu. By contrast, HER-2/neu-overexpressing SK-BR-3 cells were insensitive to IbTX. Molecular analyses showed an absence of ß-catenin and a dose-dependent upregulation of total and phosphorylated Akt and HER-2/neu in these cells. Taken together, these studies identify ß-catenin as a putative modulator of the inhibitory actions of IbTX in sensitive breast cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , Peptides/pharmacology , Wnt Signaling Pathway , beta Catenin/metabolism , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/antagonists & inhibitors , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism , Wnt Signaling Pathway/drug effects , beta Catenin/geneticsABSTRACT
In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. Importantly, the mechanisms that facilitate such infiltration or a subsequent immune suppression are not fully understood. Hence, in this study, we aimed to delineate disparate molecular pathways which MDSC utilize in murine models of colon or breast cancer. Using pathways enrichment analysis, we completed interactome maps of multiple signaling pathways in CD11b+/Gr1(high/low) MDSC from spleens and tumor infiltrates of mice with c26GM colon cancer and tumor infiltrates of MDSC in 4T1 breast cancer. In both cancer models, infiltrating MDSC, but not CD11b+ splenic cells, have been found to be enriched in multiple signaling molecules suggestive of their enhanced proliferative and invasive phenotypes. The interactome data has been subsequently used to reconstruct a previously unexplored regulation of MDSC cell cycle by the c-myc transcription factor which was predicted by the analysis. Thus, this study represents a first interactome mapping of distinct multiple molecular pathways whereby MDSC sustain cancer progression.
Subject(s)
Breast Neoplasms/pathology , Colonic Neoplasms/pathology , Mammary Neoplasms, Experimental/pathology , Myeloid Cells/pathology , Animals , Breast Neoplasms/genetics , Breast Neoplasms/immunology , CD11b Antigen/biosynthesis , CD11b Antigen/immunology , Cell Line, Tumor , Colonic Neoplasms/genetics , Colonic Neoplasms/immunology , Disease Models, Animal , Female , Gene Expression Profiling , Humans , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/immunology , Mice , Mice, Inbred BALB C , Myeloid Cells/immunology , Signal Transduction , Spleen/immunology , Spleen/pathology , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) modulate progression of certain solid tumors. The G-CSF- or GM-CSF-secreting cancers, albeit not very common are, however, among the most rapidly advancing ones due to a cytokine-mediated immune suppression and angiogenesis. Similarly, de novo angiogenesis and vasculogenesis may complicate adjuvant use of recombinant G-CSF or GM-CSF thus possibly contributing to a cancer relapse. Rapid diagnostic tools to differentiate G-CSF- or GM-CSF-secreting cancers are not well developed therefore hindering efforts to individualize treatments for these patients. Given an increasing utilization of adjuvant G-/GM-CSF in cancer therapy, we aimed to summarize recent studies exploring their roles in pathophysiology of solid tumors and to provide insights into some complexities of their therapeutic applications.
