6 research outputs found
Irradiation of Epithelial Carcinoma Cells Upregulates Calcium-Binding Proteins That Promote Survival under Hypoxic Conditions
Hypoxia is thought to promote tumor
radio-resistance via effects
on gene expression in cancer cells that modulate their metabolism,
proliferation, and DNA repair pathways to enhance survival. Here we
demonstrate for the first time that under hypoxic condition A431 epithelial
carcinoma cells exhibit increased viability when exposed to low-dose
γ-irradiation, indicating that radiotherapy can promote tumor
cell survival when oxygen supply is limited. When assessed using iTRAQ
quantitative proteomics and Western blotting, irradiated tumor cells
were observed to significantly up-regulate the expression of calcium-binding
proteins CALM1, CALU, and RCN1, suggesting important roles for these
mediators in promoting tumor cell survival during hypoxia. Accordingly,
shRNA-knockdown of CALM1, CALU, and RCN1 expression reduced hypoxic
tumor cell resistance to low-dose radiation and increased apoptosis.
These data indicate that γ-irradiation of hypoxic tumor cells
induces up-regulation of calcium-binding proteins that promote cancer
cell survival and may limit the efficacy of radiotherapy in the clinic
Mitochondrial-Targeting MET Kinase Inhibitor Kills Erlotinib-Resistant Lung Cancer Cells
Lung
cancer cells harboring activating EGFR mutations acquire resistance
to EGFR tyrosine kinase inhibitors (TKIs) by activating several bypass
mechanisms, including MET amplification and overexpression. We show
that a significant proportion of activated MET protein in EGFR TKI-resistant
HCC827 lung cancer cells resides within the mitochondria. Targeting
the total complement of MET in the plasma membrane and mitochondria
should render these cells more susceptible to cell death and hence
provide a means of circumventing drug resistance. Herein, the mitochondrial
targeting triphenylphosphonium (TPP) moiety was introduced to the
selective MET kinase inhibitor PHA665752. The resulting TPP analogue
rapidly localized to the mitochondria of MET-overexpressing erlotinib-resistant
HCC827 cells, partially suppressed the phosphorylation (Y1234/Y1235)
of MET in the mitochondrial inner membrane and was as cytotoxic and
apoptogenic as the parent compound. These findings provide support
for the targeting of mitochondrial MET with a TPP-TKI conjugate as
a means of restoring responsiveness to chemotherapy
Unique Triphenylphosphonium Derivatives for Enhanced Mitochondrial Uptake and Photodynamic Therapy
In
this study, unique methyl-functionalized derivatives (T*PP<sup>+</sup>) of the drug carrier triphenylphosphonium (TPP<sup>+</sup>) that
exhibit significant enhancement of the accumulation of both
the cation and its conjugated cargo in cell mitochondria are designed.
We show that the presence of methyl group(s) at key positions within
the phenyl ring results in an increase in the hydrophobicity and solvent
accessible surface area of T*PP<sup>+</sup>. In particular, when the <i>para</i> position of the phenyl ring in T*PP<sup>+</sup> is
functionalized with a methyl group, the cation is most exposed to
the surrounding environment, leading to a large decrease in water
entropy and an increase in the level of van der Waals interaction
with and partition into a nonpolar solvent. Therefore, stronger binding
between the hydrophobic T*PP<sup>+</sup> and mitochondrial membrane
occurs. This is exemplified in a (hexachloro-fluorescein)–TPP<sup>+</sup> conjugate system, where an ∼12 times increase in the
rate of mitochondrial uptake and a 2 times increase in photodynamic
therapy (PDT) efficacy against HeLa and FU97 cancer cells are achieved
when TPP<sup>+</sup> is replaced with T*PP<sup>+</sup>. Importantly,
nearly all the FU97 cells treated with the (hexachloro-fluorescein)–T*PP<sup>+</sup> conjugate are killed as compared to only half the population
of cells in the case of the (hexachloro-fluorescein)–TPP<sup>+</sup> conjugate at a similar PDT light dosage. This study thus
forms a platform for the healthcare community to explore alternative
TPP<sup>+</sup> derivatives that can act as optimal drug transporters
for enhanced mitochondrially targeted therapies
Inflation channels in the structure of monetary transmission
У мoнографії висвітлені основні напрями формування монетарної політики держави, розкрито сутність стратегії інфляційного таргетування.The book considers the basic ways of establishing the monetary policy of the country. The essentials of the inflation targeting are disclosed in details
Multidimensional Identification of Tissue Biomarkers of Gastric Cancer
Gastric cancer remains highly fatal due to a dearth of
diagnostic
biomarkers for early stage disease and molecular targets for therapy.
Plasma membrane proteins, including cluster of differentiation (CD)
proteins and receptor tyrosine kinases (RTKs), are a rich reservoir
of biomarkers. Recognizing that interrogating plasma membrane proteins
individually overlooks extensive interactions among them, we have
systematically investigated the membrane proteomes and transcriptomes
of six gastric cancer cell lines. Our data revealed aberrantly high
expression of proteins whose functions accurately reflect the clinical
phenotype of gastric cancer, and prioritized critical RTKs and CD
proteins in gastric cancer. Expression of selected surface proteins
was confirmed by flow cytometry and immunostaining of clinical gastric
cancer tissues. Close to 90% of the gastric cancer tissues in a cohort
showed up-regulation of at least one of four proteins, that is, MET,
EPHA2, FGFR2, and CD104/ITGB4. All intestinal type gastric cancer
tumors in this cohort overexpressed at least one of a panel of three
proteins, MET, FGFR2, and EPHA2. This study reports the first quantitative
global landscape of the surface proteome of gastric cancer cells and
provides a shortlist of gastric cancer biomarkers
Multidimensional Identification of Tissue Biomarkers of Gastric Cancer
Gastric cancer remains highly fatal due to a dearth of
diagnostic
biomarkers for early stage disease and molecular targets for therapy.
Plasma membrane proteins, including cluster of differentiation (CD)
proteins and receptor tyrosine kinases (RTKs), are a rich reservoir
of biomarkers. Recognizing that interrogating plasma membrane proteins
individually overlooks extensive interactions among them, we have
systematically investigated the membrane proteomes and transcriptomes
of six gastric cancer cell lines. Our data revealed aberrantly high
expression of proteins whose functions accurately reflect the clinical
phenotype of gastric cancer, and prioritized critical RTKs and CD
proteins in gastric cancer. Expression of selected surface proteins
was confirmed by flow cytometry and immunostaining of clinical gastric
cancer tissues. Close to 90% of the gastric cancer tissues in a cohort
showed up-regulation of at least one of four proteins, that is, MET,
EPHA2, FGFR2, and CD104/ITGB4. All intestinal type gastric cancer
tumors in this cohort overexpressed at least one of a panel of three
proteins, MET, FGFR2, and EPHA2. This study reports the first quantitative
global landscape of the surface proteome of gastric cancer cells and
provides a shortlist of gastric cancer biomarkers