The Role of Protein Synthesis in the Senescence of …
The intratumoral metabolism and synthesis ofestrogens, as a result of the interactions of various enzymes, isconsidered to play an important role in the pathogenesis anddevelopment of hormone-dependent breast carcinoma (–).In breast cancer, particularly that of postmenopausal women,estrogens are synthesized in the mammary tissue by transformationeither from androgen precursors, mainly of adrenal origin, or frombiologically inactive estrogens. Breast carcinoma epithelial cellscontain all the enzymes necessary for the local synthesis ofestrogens (). One of themajor pathways involved in the synthesis of estrogens in breastcancer cells is the aromatase pathway, which transforms androgensinto estrogens (). Aromataseactivity and expression is markedly higher in breast cancer tissuethan in normal mammary tissue (,).The second pathway involved in estrogen formation is the sulfatasepathway, which converts estrogen sulfates into estrone andestradiol (,,).The final step of steroidogenesis in peripheral tissues is theconversion of the weak estrone to the potent biologically activeestradiol by the action of the 17β-hydroxysteroid dehydrogenaseactivity type 1 (17β-HSD1) (,).In breast cancer tissue, estrogen sulfotransferase is also present,which converts estrogens into estrogen sulfates. Since thesulfo-conjugated estrogens are the biologically inactive forms ofthe estrogens, another possible way to control the tissularconcentration of active estradiol is to identify new ways tostimulate the enzymes involved in the sulfate formation (,).
Possible Role of Proteolytic Enzymes in Protein Synthesis
Melatonin may play a role in the paracrineinteractions that take place between malignant epithelial cells andproximal endothelial cells, acting by different mechanisms. On onehand, melatonin exerts antiangiogenic effects and may be importantin reducing endothelial cell proliferation, invasion, migration andtube formation, through a downregulatory action on VEGF andPGE ().PGE synthesis induced by VEGF may directly promoteangiogenesis and melatonin through its downregulatory action on theexpression of COX enzymes, which decrease the levels ofPGE and reduce angiogenesis. On the other hand,melatonin inhibits aromatase activity and expression in endothelialcells by regulating gene expression of specific aromatase promoterregions, thereby reducing the local production of estrogens().
Cells have evolved complex regulatory mechanisms toadapt the metabolism to various physiological states. Rapidlygrowing cells consume nutrients at a high rate and must maintain abalance between the utilization of nutrients for ATP synthesis andanabolic development, including protein, lipid and nucleic acidsynthesis. Cancer cells use glucose at higher rates compared tonon-cancerous cells, but use a smaller fraction for oxidativephosphorylation, which enables cancer cells to incorporate agreater fraction of glucose metabolites in macromolecule synthesisinstead of expending it on carbon dioxide production (,).Consequently, metabolic programming of cancer cells is required tobe flexible, which allows the cells to adapt to variousenvironmental conditions. PKM2 is responsible for the final step ofglycolysis and is key in this process (,). Thepreferential expression and allosteric enzymatic activity of PKM2provides the cancer cells with a growth advantage ,without the accumulation of ROS.
30/12/2017 · Protein; 5 Roles of Protein
PKM2 acts as a proliferative agent through itsinteraction with nuclear proteins, and as a differentiating agentthrough its interaction with octamer-binding transcription factor 4(Oct4), which is a key regulator in cancer stem cell self-renewaland differentiation (). In gliomastem cells, the interaction between PKM2 and Oct4 inhibits theability of PKM2 to maintain cell stemness, thereby promoting celldifferentiation and enhancing the sensitivity of cells to celldeath, which is concomitant with an alteration between the dimerand tetramer states of PKM2 ().Notably, dichloroacetate, which is known as an inhibitor of PDK1and is involved in the mitochondrial tricarboxylic acid cycle,increases the number of PKM2/Oct4 complexes ().
quiz protein synthesis - Biology Junction
PKM2 not only acts as a coactivator, but may alsoact as a protein kinase that phosphorylates substrates involved inmetabolic reprogramming. Nuclear dimeric PKM2 directlyphosphorylates signal transducer and activator of transcription 3(STAT3), which is activated in response to inflammatory cytokines,including interleukin-6 (). PKM2uses PEP as a phosphate donor to phosphorylate STAT3 attyrosine-705, which activates the transcription ofmitogen-activated protein kinase kinase 5. The activation of STAT3in malignant cancer cells is possibly one of the most importantmolecular signatures for promoting the progression of cancer. PKM2overexpression facilitates STAT3 nuclear translocation, whichregulates the aggressive progression of colorectal cancer (). The functional implications of thestudy by Yang ()indicate that PKM2 activates β1-integrin-focal adhesion kinase andsnail-2-E-cadherin signaling, and also upregulates the expressionof matrix metalloproteinase-2 and 9, which induces cell migrationand adhesion. Similarly to STAT3, histone H3 is a substrate forPKM2 kinase activity (). PKM2directly binds and phosphorylates histone H3 at threonine-11, whichleads to the removal of HDAC3 from CCND1 and Myc promoter regions,subsequent to acetylation at lysine-9 and gene transcription(). PKM2-dependent histone H3modifications are key to EGF stimulation (). Furthermore, nuclear PKM2 levels areassociated with phosphorylation at proline-3/threonine-11 inmalignant glioma (). Recently, astudy reported that the PKM2-SAICAR interaction is required andsufficient to induce robust protein kinase activity in PKM2 and in cancer cells ().It was also reported that the PKM2-SAICAR complex phosphorylates>100 human proteins, the majority of which were previouslyunrecognized. In particular, PKM2-SAICAR directly activates ERK1; however, activated ERK1/2 phosphorylates PKM2,creating a positive feedback loop (). Additionally, when EGFR is activated,the concentration of cellular SAICAR is increased, which isrequired to sustain the activation of ERK1/2 and proliferativesignaling via PKM2 ().
Protein Synthesis -Translation and Regulation
Endothelial cells also represent a critical cellularelement in the tumor microenvironment, which play a crucial role inthe growth and progression of breast tumors. They are anothersource of estrogens, as they also express aromatase (,).Promoter I.7 is a novel breast cancer-associated aromatase promotermainly active in vascular endothelial cells, and is upregulated inbreast cancer tissue ().Excessive aromatase expression via promoters I.3, II and I.7, andconsequent increase in estrogen biosynthesis in malignantepithelial cells, undifferentiated adipose fibroblasts and adjacentendothelial cells contribute to the development and progression ofbreast cancer. In addition, endothelial cells provide structuraland biochemical support for tumor growth and progression of cancerthrough control of angiogenesis. Vascular endothelial growth factor(VEGF) secreted by breast cancer cells is essential for theexpansion of breast cancer and may function in both paracrine andautocrine manners to promote the proliferation, growth, survivaland migration of endothelial cells (,).