Germanium inhibits proliferation, induces apoptosis, and inhibits metastatic potential via inhibition of MMP-9 expression and through suppressed extracellular pathway signaling of the PI3K/Akt and ERK 1/2 pathways.
High density level of PGR in the TE was an independent prognostic factor for CF.
Our large-sized study demonstrates a wide distribution of PGR in stromal and epithelial cells of both benign and malignant prostate tissue
there seems to be a general agreement of PGR presence in the stromal cells of PCa
In line with our findings, several have also reported a high PGR expression in TE of PCa [9,10,23,25]. In contrast, others have demonstrated a total lack of PGR expression in TE
the actions of progesterone are tissue specific
In our work univariate analysis demonstrated a high PGR expression in TS to be associated with clinical failure in PCa patients. So far we have not yet demonstrated the mechanism underlying this association
Several non-genomic proliferative actions of progesterone have been proposed in tumor cells of other organs, including breast [35–37], astrocytoma [38] and osteosarcoma [39] cell lines. However, such results are contradicted by suggestions of anti-proliferative actions of progesterone in endometrial cancer
Yu et al. found PGR to be negatively regulating stromal cell proliferation in vitro
high PGR density level in TE was associated with CF in patients with Gleason score ≥ 7
Bonkhoff et al. have suggested progressive emergence of PGR during PCa progression and metastasis
Latil and co-workers found a decreased PGR expression in clinically localized tumors and increased PGR expression in hormone-refractory tumors, when compared with normal prostate tissue
Our findings provide further support to these findings, indicating that PGR plays a role in the pathogenesis of PCa
Ki67 and PGR in TE were correlated with CF (S3 Text), indicating an association between PGR and proliferative activity
The mechanism behind the PGR up-regulation in PCa has not yet been elucidated
The PGR is, like the glucocorticoid receptor, similar to androgen receptor with 88% sequence homology in the ligand-binding domain
progesterone induced expression of androgen receptor-regulated genes could be a potential mechanism contributing to the development of castrate resistant PCa
A possibility of different roles by the two PGR isoforms in normal prostate tissue and PCa, as is suggested for the estrogen receptors [13], must also be taken into account
STudy finds that increased Progesterone receptor expression on epithelial and stromal cells is associated with increased clinical failure of therapy. Several proposed mechanisms: 88% homologous with androgen receptor suggesting cross-stimulation and via progesterone induced increased androgen receptor gene stimulation i.e. epigenetics.
The switch may also involve down-regulation of endogenous inhibitors of angiogenesis such as endostatin, angiostatin or thrombospondin (reviewed in [5]) and has thus been regarded as the result of tipping the net balance between positive and negative regulators
There is a complex interrelationship between tumor hypoxia and tumor angiogenesis
Environmental stress as a result of low oxygen and proper nutrient deprivation, such as glucose deprivation, are capable of inducing VEGF mRNA stabilization resulting in increased levels of the secreted ligand and angiogenic growth
HIFalpha subunits accumulate in the cytoplasm where they bind HIFbeta to form a heterodimer that subsequently translocates to the nucleus to activate transcription of target genes, including genes important for various processes such as metabolism (glucose transporter (GLUT)-1, hexokinase (HK)-1), cell growth (cyclin (CCN)-D1 [23]) and also angiogenesis, such as erythropoietin, VEGF and PDGF [24] (summarized in Fig. 1)
When oxygen levels are low (hypoxia; red arrow) PHDs cannot hydroxylate HIFalphas thereby allowing them to escape pVHL-mediated degradation. HIFalpha subunits accumulate and bind to their heterodimeric partner, HIFbeta, translocate into the nucleus and activate a cascade of hypoxic signaling first by the transcription of various target genes including microRNAs that are important for tumor promoting pathways
c-Src is also capable of activating HIFs by indirectly inhibiting PHD activity via the NADPH oxidase/Rac pathway.
mTOR can also promote stabilization and HIF transcriptional activity
hypoxia inducible factors (HIFs), heterodimeric transcription factors composed from alpha and beta subunits, which can be rapidly stabilized to fluidly adapt to and overcome the effects of a hypoxic environment
Curcumin inhibits the expression of epidermal growth factor receptor (EGFR), VEGFR-1, VEGFR-2 and VEGFR-3, and the kinase activity of Src and FAK, which are responsible for the induction of angiogenic genes as well as endothelial cell polarity and migration
Curcumin also reduces the MMP-2 and MMP-9 expression, along with the suppression of growth and invasion potential of tumor cells in culture and xenograft experiments
The expression of angiogenic biomarkers COX-2 and serum levels of VEGF were significantly reduced in the curcumin-treated group
Resveratrol inhibits capillary endothelial cell growth and new blood vessel growth in animals
[155] and impeding angiogenesis by suppressing VEGF expression through down-regulation of HIF-1alpha
resveratrol was reported to inhibit cell proliferation of human ovarian cancer cells and human osteosarcoma cells by attenuating HIF-1alpha
prevents cytokine-induced vascular leakage and tumor metastasis
The underlying molecular mechanisms include: blocking VEGF- and FGF-receptor-mediated MAPK activation, inhibiting Akt- and MAPK-driven HIF-1alpha basal expression and its induction by IGF-1, stimulating the proteasomal degradation of HIF-1alpha, inhibiting phosphatidyl inositol (PI)-3K/Akt and Ras/mitogen/extracellular signal-regulated kinase (MEK)/ERK pathways, and activation of forkhead box (FOX)O transcription factors