10 research outputs found
Role of PLEXIND1/TGFβ signaling axis in pancreatic ductal adenocarcinoma progression correlates with the mutational status of KRAS
PLEXIND1 is upregulated in several cancers, including pancreatic ductal adenocarcinoma (PDAC). It is an established mediator of semaphorin signaling, and neuropilins are its known coreceptors. Herein, we report data to support the proposal that PLEXIND1 acts as a transforming growth factor beta (TGFβ) coreceptor, modulating cell growth through SMAD3 signaling. Our findings demonstrate that PLEXIND1 plays a pro-tumorigenic role in PDAC cells with oncogenic KRAS (KRASmut). We show in KRASmut PDAC cell lines (PANC-1, AsPC-1,4535) PLEXIND1 downregulation results in decreased cell viability (in vitro) and reduced tumor growth (in vivo). Conversely, PLEXIND1 acts as a tumor suppressor in the PDAC cell line (BxPC-3) with wild-type KRAS (KRASwt), as its reduced expression results in higher cell viability (in-vitro) and tumor growth (in vivo). Additionally, we demonstrate that PLEXIND1-mediated interactions can be selectively disrupted using a peptide based on its C-terminal sequence (a PDZ domain-binding motif), an outcome that may possess significant therapeutic implications. To our knowledge, this is the first report showing that (1) PLEXIND1 acts as a TGFβ coreceptor and mediates SMAD3 signaling, and (2) differential roles of PLEXIND1 in PDAC cell lines correlate with KRASmut and KRASwt status
<p>Co-delivery of everolimus and vinorelbine via a tumor-targeted liposomal formulation inhibits tumor growth and metastasis in RCC</p>
Dopamine regulates phosphorylation of VEGF receptor 2 by engaging Src-homology-2-domain-containing protein tyrosine phosphatase 2
Vascular endothelial growth factor (VEGF)-induced receptor phosphorylation
is the crucial step for initiating downstream signaling pathways that lead to
angiogenesis or related pathophysiological outcomes. Our previous studies have
shown that the neurotransmitter dopamine could inhibit VEGF-induced
phosphorylation of VEGF receptor 2 (VEGFR-2), endothelial cell proliferation,
migration, microvascular permeability, and thus, angiogenesis. In this study,
we address the mechanism by which VEGFR-2 phosphorylation is regulated by
dopamine. Here, we demonstrate that D2 dopamine receptor (D2DR) colocalizes
with VEGFR-2 at the cell surface. Dopamine pretreatment increases the
translocation and colocalization of Src-homology-2-domain-containing protein
tyrosine phosphatase (SHP-2) with D2DR at the cell surface. Dopamine
administration leads to increased VEGF-induced phosphorylation of SHP-2 and
this increased phosphorylation parallels the increased phosphatase activity of
SHP-2. Active SHP-2 then dephosphorylates VEGFR-2 at Y951, Y996 and Y1059, but
not Y1175. We also observe that SHP-2 knockdown impairs the dopamine-regulated
inhibition of VEGF-induced phosphorylation of VEGFR-2 and, subsequently, Src
phosphorylation and migration. Our data establish a novel role for SHP-2
phosphatase in the dopamine-mediated regulation of VEGFR-2
phosphorylation
Glucocorticoid Receptor-Targeted Liposomal Codelivery of Lipophilic Drug and Anti-Hsp90 Gene: Strategy to Induce Drug-Sensitivity, EMT-Reversal, and Reduced Malignancy in Aggressive Tumors
Many
cancers including the late stage ones become drug-resistant and undergo
epithelial-to-mesenchymal transition (EMT). These lead to enhanced
invasion, migration, and metastasis toward manifesting its aggressiveness
and malignancy. One of the key hallmarks of cancer is its overdependence
on glycolysis as its preferred energy metabolism pathway. The strict
avoidance of alternate energy pathway gluconeogenesis by cancer cells
points to a yet-to-be hoisted role of glucocorticoid receptor (GR)
especially in tumor microenvironment, where cells are known to become
drug-sensitive through induction of gluconeogenesis. However, since
GR is involved in metabolism, anti-inflammatory reactions, immunity
besides inducing gluconeogenesis, a greater role of GR in tumor microenvironment
is envisaged. We have shown previously that GR, although ubiquitously
expressed in all cells; afford to be an effective cytoplasmic target
for killing cancer cells selectively. Herein, we report the therapeutic
use of a newly developed GR-targeted liposomal concoction (DXE) coformulating
a lipophilic drug (ESC8) and an anti-Hsp90 anticancer gene against
aggressive tumor models. This induced drug-sensitivity and apoptosis
while reversing EMT in tumor cells toward effective retardation of
aggressive growth in pancreas and skin tumor models. Additionally,
the ESC8-free lipid formulation upon cotreatment with hydrophilic
drugs, gemcitabine and doxorubicin, could effectively sensitize and
kill pancreatic cancer and melanoma cells, respectively. The formulation-triggered
EMT-reversal was GR-dependent. Overall, we found a new strategy for
drug sensitization that led to the advent of new GR-targeted anticancer
therapeutics
Inhibition of endoglin-GIPC interaction inhibits pancreatic cancer cell growth
Endoglin, a 180-kDa disulfide-linked homodimeric transmembrane receptor protein mostly expressed in tumor-associated endothelial cells, is an endogenous binding partner of GAIP-interacting protein, C terminus (GIPC). Endoglin functions as a coreceptor of TβRII that binds TGFβ and is important for vascular development and consequently has become a compelling target for antiangiogenic therapies. A few recent studies in Gastrointestinal Stromal Tumor (GIST), breast cancer and ovarian cancer, however, suggest that endoglin is upregulated in tumor cells and is associated with poor prognosis. These findings indicate a broader role of endoglin in tumor biology, beyond angiogenic effects. The goal of our current study is to evaluate the effects of targeting endoglin in pancreatic cancer both in vitro and in vivo. We analyzed the antiproliferative effect of both RNAi-based and peptide ligand-based inhibition of endoglin in pancreatic cancer cell lines, the latter yielding a GIPC PDZ domain-targeting lipopeptide with notable antiproliferative activity. We further demonstrated that endoglin inhibition induced a differentiation phenotype in the pancreatic cancer cells and sensitized them against conventional chemotherapeutic drug gemcitabine. Most importantly, we have demonstrated the antitumor effect of both RNAi-based and competitive inhibitor–based blocking of endoglin in pancreatic cancer xenograft models in vivo. To our knowledge, this is the first report exploring the effect of targeting endoglin in pancreatic cancer cells