جراح و متخصص بیماریهای کلیه ومجاری ادرار ازدانشکده پزشکی دانشگاه تهران و عضو انجمن ارولوژی ایران
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Tue 1 Oct 2013



ارسال شده توسط دکتر محمد هزارخانی در ساعت 1:16 بعد از ظهر |
Sat 16 Jul 2011

In The Name Of God

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           The Books That Authored And Translated by

                            Mohammad Hezarkhani                    

 

ارسال شده توسط دکتر محمد هزارخانی در ساعت 3:32 بعد از ظهر
Tue 15 Jul 2014

  

Edited by:Mohammad  Hezarkhani  MD,Urologist

Board-Certified of Urology,Tehran  University ,The Member  of  Iranian  Urological  Association

Madaen Hospital  Tehran Iran

Tehranclinic  Hospital Tehran Iran

Mohammad.hezarkhani@yahoo.com

www.Hezarkhani.blogfa.com  hosted in Washington DC, United States

July 15. 2014 

The phosphatases of regenerating liver (PRLs) are a unique family of plasma membrane-associated protein tyrosine phosphatases that have been hypothesized to be involved in metastatic cancer. How PRLs control cancer cell migration, invasion, and proliferation remains largely unknown. In the current study, researcher demonstrate a role for PRL-1 in the regulation of filamentous actin dynamics, which could promote cell metastatic processes. 

Human A549 non–small-cell lung cancer cells stably expressing wild-type PRL-1 exhibited a 60% increase in migration and a 3-fold increase in invasion. Cells expressing catalytic mutants of PRL-1 (C104S and D72A) lacked increased cell migration and invasion, indicating that these phenotypic changes required PRL-1 phosphatase activity. In contrast, PRL-1 small interfering RNA decreased in vitro lung cancer cell migration and invasion. The cadherin-catenin complex and dynamic filamentous actin are believed to control cellular invasiveness. Expression of wild-type PRL-1, but not phosphatase-inactive PRL-1 (C104S or D72A), decreased E-cadherin, vinculin, and paxillin expression. 

Ectopic expression of wild-type PRL-1 increased RhoA levels, which have an important role in actin filament assembly and stabilization of focal adhesion, and decreased activated Cdc42 and Rac. The Rho-associated protein kinase inhibitor, (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride (Y-27632), decreased RhoA activity, actin filament levels, and cellular migration and invasion in PRL-1-expressing cells. These results suggest that PRL-1 could be a productive cancer therapeutic target and support further efforts to identify its substrates. 

In the United States, lung cancer is the leading cause of cancer-related deaths in both men and women, accounting for >165,000 deaths per year, and it is predicted to become the leading cause of death worldwide .The 5-year survival rate remains at <15%, even though there have been numerous attempts to control mortality from lung cancer.The fundamental cause of patient death is the invasive and metastatic properties of tumors, processes about which we have incomplete understanding and for which we have no targeted drugs. 

Tumor cell invasion and metastasis are dynamic cellular processes that extensively exploit phospho-relay signaling systems. The central role of abnormal protein tyrosine phosphorylation in human cancers is well accepted. The phosphatases of regenerating liver (PRLs) family represents a unique protein tyrosine phosphatase (PTP) subfamily with its three family members (PRL-1, PRL-2, and PRL-3) being the only PTPs that are subject to prenylation. Emerging evidence supports a role for PRLs in the basic biology of cancer cell development and metastasis . 

Although chemotherapy for castration-resistant prostate cancer (CRPC) has been applied clinically in recent years, the effects are not sufficient. It is urgently necessary to develop novel therapeutics for CRPC. We previously generated Escherichia coli ampicillin secretion trap libraries of 2 prostate cancer (PCa) cell lines and normal prostate. By comparing the E. coli ampicillin secretion trap libraries of CRPC cell lines with those of androgen-sensitive PCa cell lines and normal prostate, we focused on the protein-tyrosine-phosphatase of regenerating liver 1 (PRL1) gene and analyzed its expression and biological function. 

Quantitative reverse transcription polymerase chain reaction revealed that PRL1 was expressed much more highly in PCa than in nonneoplastic prostate samples. High expression of PRL1 detected by immunohistochemistry correlated with poor prognosis after prostatectomy and combined androgen blockade therapy. Functional analysis indicated that PRL1 stimulated cell growth, migration, and invasion in PCa cell lines. Expression EGFR and matrix metalloproteinase 9 was reduced by knockdown of PRL1 in the PC3 cell line.

PRL1 regulates expression of EGFR and modulates downstream targets. PRL1 has potential as a therapeutic target in PCa including CRPC. 

References:

1- Identification of PRL1 as a novel diagnostic and therapeutic target for castration-resistant prostate cancer by the Escherichia coli ampicillin secretion trap (CAST) method 

Shunsuke Shinmei, M.D.abKazuhiro Sentani, M.D., Ph.D.aTetsutaro Hayashi, M.D., Ph.D.bNaoya Sakamoto, M.D., Ph.D.aKeisuke Goto, M.D.abHtoo Zarni Oo, M.D., Ph.D.aYutaka Naito, Ph.D.aJun Teishima, M.D., Ph.D.bAkio Matsubara, M.D., Ph.D.bNaohide Oue, M.D., Ph.D.aHiroki Kuniyasu,M.D., Ph.D.cWataru Yasui, M.D., Ph.D.a, ,  DOI: 10.1016/j.urolonc.2014.03.007

Urologic Oncology: Seminars and Original Investigations

2-Phosphatase of Regenerating Liver-1 Promotes Cell Migration and Invasion and Regulates Filamentous Actin Dynamics 

Masanao Nakashima and John S. Lazo/Department of Pharmacology and Chemical Biology, Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 

ارسال شده توسط دکتر محمد هزارخانی در ساعت 10:34 بعد از ظهر |
Tue 15 Jul 2014

                     

Physical activity and benign prostatic hyperplasia-related outcomes and nocturia Medicine and Science in Sports and Exercise, July 15, 2014      

Initial biopsy Gleason score as a predictive marker for survival benefit in patients with castration-resistant prostate cancer treated with docetaxel: Data from the TAX327 study Full Text European Urology, July 15, 2014      

KLK3, PCA3, and TMPRSS2-ERG expression in the peripheral blood mononuclear cell fraction from castration-resistant prostate cancer patients and response to docetaxel treatment The Prostate, July 15, 2014   

Topography of lymph node metastases in prostate cancer patients undergoing radical prostatectomy and extended lymphadenectomy: Results of a combined molecular and histopathologic mapping study Full Text European Urology, July 15, 2014       

Identification of PRL1 as a novel diagnostic and therapeutic target for castration-resistant prostate cancer by the Escherichia coli ampicillin secretion trap (CAST) method Urologic Oncology: Seminars and Original Investigations, July 15, 2014  

ارسال شده توسط دکتر محمد هزارخانی در ساعت 8:57 بعد از ظهر |
Mon 14 Jul 2014

 

P

Enzalutamide Before Chemotherapy Reduces Cancer Progression Risk

PSA Decline is a Potential Biomarker for Identifying Early Resistance to Zytiga and Xtandi In Men Who are Post Chemotherapy

Anticoagulants May Increase Survival in Men with Advanced Prostate Cancer Taking Chemotherapy

Automated quantitative multiplex immunofluorescence in situ imaging identifies phospho-S6 and phospho-PRAS40 as predictive protein biomarkers for prostate cancer lethality

The tyrosine kinase inhibitor nilotinib has antineoplastic activity in prostate cancer cells but up-regulates the ERK survival signal-Implications for targeted therapies.

Karyopharm begins Phase II trial of hormone refractory prostate cancer drug Selinexor

A novel small molecule hybrid of vorinostat and DACA displays anticancer activity against human hormone-refractory metastatic prostate cancer through dual inhibition of histone deacetylase and topoisomerase I.

New metastasis-suppressor gene identified by cancer researchers

Depressed men with prostate cancer are diagnosed with later stage disease, and get less effective therapies

Vasectomy may increase risk of aggressive prostate cancer

Variations in key gene predict cancer patients' risk for radiation-induced toxicity

 

 

 

ارسال شده توسط دکتر محمد هزارخانی در ساعت 10:36 بعد از ظهر |
Sun 13 Jul 2014

Urology news  July 13, 2014

July 9, 2014

Vasectomy was associated with a small increased risk of prostate cancer, and a stronger risk for advanced or lethal prostate cancer according to a new study from Harvard School of Public Health (HSPH). The researchers found that the association remained even among men who received regular PSA screening, suggesting the increased risk of lethal cancer cannot be explained by diagnostic bias. It is the largest and most comprehensive study to date to look at the link between vasectomy and prostate cancer.

"This study follows our initial publication on vasectomy and prostate cancer in 1993, with 19 additional years of follow-up and tenfold greater number of cases. The results support the hypothesis that vasectomy is associated with an increased risk of advanced or lethal prostate cancer," said co-author Lorelei Mucci, associate professor of epidemiology at HSPH.

Vasectomy is a common form of contraception in the U.S., with about 15% of men having the procedure. Prostate cancer is the second-leading cause of cancer death among U.S. men, so identifying risk factors for lethal prostate cancer is important for public health.

The researchers analyzed data from 49,405 U.S. men in the Health Professionals Follow-up Study, who were followed for up to 24 years from 1986 to 2010. During that time, 6,023 cases of prostate cancer were diagnosed, including 811 lethal cases. One in four of the men in this study reported having a vasectomy.

The results showed a 10% increased risk of prostate cancer overall in men who had a vasectomy. Vasectomy was not significantly associated with risk of low-grade cancer. However, vasectomy was associated with a stronger risk of advanced and lethal prostate cancer, with an increased risk of 20% and 19% respectively. Among men who received regular PSA screening, the relative increase in risk of lethal prostate cancer was 56%. The effect appeared to be stronger among men who had a vasectomy at a younger age.

Prior work on this topic raised concerns that the positive associations could be linked to bias. However, in the present study, the researchers had access to diverse information and could rule out potential biases, including that men who have vasectomies may seek more medical care in general, that they may have a higher rates of PSA screening, or that the association was due possible confounding by sexually transmitted infections.

In this study, 16 in 1,000 men developed lethal prostate cancer during 24 years of follow-up. Although the relative increase in the risk associated with vasectomy was significant, this translates to a relatively small increase in absolute difference in the risk of lethal prostate cancer, say the researchers. "The decision to opt for a vasectomy as a form of birth control is a highly personal one and a man should discuss the risks and benefits with his physician," said co-author Kathryn Wilson, research associate in the Department of Epidemiology at HSPH.

Story Source: Harvard School of Public Health.

Journal Reference:Mohummad Minhaj Siddiqui, Kathryn M. Wilson, Mara M. Epstein, Jennifer R. Rider, Neil E. Martin, Meir J. Stampfer, Edward L. Giovannucci, Lorelei A. Mucci. Vasectomy and risk of aggressive prostate cancer: a 24-year follow-up study. Journal of Clinincal Oncology, July 2014 DOI: 10.1200/JCO 2013.54.8446

 

ارسال شده توسط دکتر محمد هزارخانی در ساعت 9:7 بعد از ظهر |
Tue 8 Jul 2014

 

Edited by:Mohammad  Hezarkhani  MD,Urologist

Board-Certified of Urology,Tehran  University ,The Member  of  Iranian  Urological  Association

Madaen Hospital  Tehran Iran

Tehranclinic  Hospital Tehran Iran

Mohammad.hezarkhani@yahoo.com

www.Hezarkhani.blogfa.com  hosted in Washington DC, United States

July 07. 2014

Nucleoporin p62 (p62) is a protein complex associated with the nuclear envelope. The p62 protein remains associated with the nuclear pore complex-lamina fraction. p62 is synthesized as a soluble cytoplasmic precursor of 61 kDa followed by modification that involve addition of N-acetylglucosamine residues. followed by association with other complex proteins.

The signaling adaptor p62 is a critical mediator of important cellular functions, owing to its ability to establish interactions with various signaling intermediaries. Here, we identify raptor as an interacting partner of p62. Thus, p62 is an integral part of the mTORC1 complex and is necessary to mediate amino acid signaling for the activation of S6K1 and 4EBP1.

p62 interacts in an amino acid-dependent manner with mTOR and raptor. In addition, p62 binds the Rags proteins and favors formation of the active Rag heterodimer that is further stabilized by raptor. Interestingly, p62 colocalizes with Rags at the lysosomal compartment and is required for the interaction of mTOR with Rag GTPases in vivo and for translocation of the mTORC1 complex to the lysosome, a crucial step for mTOR activation.

The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene is a member of the FG-repeat containing nucleoporins and is localized to the nuclear pore central plug. This protein associates with the importin alpha/beta complex which is involved in the import of proteins containing nuclear localization signals. Multiple transcript variants of this gene encode a single protein isoform.

P62 is a serine/threonine rich protein of ~520 amino acids, with tetrapeptide repeats on the amino terminus and a series of alpha-helical regions with hydrophobic heptad repeats.P62 assembles into a complex containing 3 addition proteins, p60, p54 and p45 , forming the p62 complex of ~235 kDa. Glycosylation appears to be involved in the assembly and disassembly of p62 into higher order complexes, and a serine/threonine rich linker region between Ser270 to Thr294 appear to be regulatory. The p62 complex is localized to both the nucleoplasmic and cytoplasmic sides of the pore complex and the relative diameter of p62 complex relative to the nuclear pore complex suggests it interacts in pore gating.

P62 appears to interact with mRNA during transport out of the nucleus. P62 also interacts with a nuclear transport factor (NTF2) protein that is involved in trafficking proteins between cytoplasm and nucleus. Another protein, importin (beta) binds to the helical rod section of p62, which also binds NTF2 suggesting the formation of a higher order gating complex. Karyopherin beta2 (transportin), a riboprotein transporter also interacts with p62. P62 also interacts with nucleoporin-93kDa, and when Nup98 is depleted p62 fails to assemble with nuclear pore complexes. Mutant pores could not dock/transport proteins with nuclear localization signals or M9 import signals.

Moscat and colleagues demonstrated that p62 activation in prostate and lung cancer epithelial cells had tumor-promoting effects. Cancers of the epithelial cells are called carcinomas, and about 85 percent of all cancers are carcinomas. These are highly significant observations since p62 activates another protein called mTOR which is a biological target of many ongoing clinical trials in cancer right now.

The initial hint that p62 in the stroma influences tumor growth came by analyzing more than 200 human prostate tumors with Gleason scores ranging from 2 to 10. Gleason scores are a numerical assignment given to prostate tumors based on pathology, with the highest scores (10 maximum) indicating that the cancer is very likely to spread. The research team found that p62 levels in the stroma were significantly lower in samples with the highest Gleason scores, suggesting a protective role for p62.

To understand how p62 works, the research team introduced prostate cancer cells and monitored tumor formation in normal mice, and mice genetically engineered to lack p62. The mice without p62, called p62 knockout (KO) mice, had larger prostate tumors compared to normal mice, supporting the notion that the absence of p62 in an organism promotes cancer growth.

The researchers went on to show that p62 KO mice had increased levels of IL-6, a pro-inflammatory cytokine (a signaling molecule) that enhances tumor cell proliferation and inhibits cell death. And, the genetic events that linked p62 depletion to increased levels of IL-6 in mice were mirrored in humans.

References:

1-Medical news today  July 07.2014

2- Nucleoporin p62,Wikipedia, the free encyclopedia  June 01, 2014

3- p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway

Angeles Duran1, 2, 3,Ramars Amanchy2, 3, Juan F. Linares1, 2, 3, Jayashree Joshi2, Shadi Abu-Baker2, Aleksey Porollo2, Malene Hansen1, Jorge Moscat1, 2, Maria T. Diaz-Meco1, 2,Molecular cell  Volume 44, Issue 1, 7 October 2011, Pages 134–146

ارسال شده توسط دکتر محمد هزارخانی در ساعت 0:13 قبل از ظهر |
Mon 7 Jul 2014

Edited by:Mohammad  Hezarkhani  MD,Urologist

Board-Certified of Urology,Tehran  University ,The Member  of  Iranian  Urological  Association

Madaen Hospital  Tehran Iran

Tehranclinic  Hospital Tehran Iran

Mohammad.hezarkhani@yahoo.com

www.Hezarkhani.blogfa.com  hosted in Washington DC, United States

July 07. 2014

Nucleoporin p62 (p62) is a protein complex associated with the nuclear envelope. The p62 protein remains associated with the nuclear pore complex-lamina fraction. p62 is synthesized as a soluble cytoplasmic precursor of 61 kDa followed by modification that involve addition of N-acetylglucosamine residues. followed by association with other complex proteins.

The signaling adaptor p62 is a critical mediator of important cellular functions, owing to its ability to establish interactions with various signaling intermediaries. Here, we identify raptor as an interacting partner of p62. Thus, p62 is an integral part of the mTORC1 complex and is necessary to mediate amino acid signaling for the activation of S6K1 and 4EBP1.

p62 interacts in an amino acid-dependent manner with mTOR and raptor. In addition, p62 binds the Rags proteins and favors formation of the active Rag heterodimer that is further stabilized by raptor. Interestingly, p62 colocalizes with Rags at the lysosomal compartment and is required for the interaction of mTOR with Rag GTPases in vivo and for translocation of the mTORC1 complex to the lysosome, a crucial step for mTOR activation.

The nuclear pore complex is a massive structure that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the nucleus and the cytoplasm. Nucleoporins are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene is a member of the FG-repeat containing nucleoporins and is localized to the nuclear pore central plug. This protein associates with the importin alpha/beta complex which is involved in the import of proteins containing nuclear localization signals. Multiple transcript variants of this gene encode a single protein isoform.

P62 is a serine/threonine rich protein of ~520 amino acids, with tetrapeptide repeats on the amino terminus and a series of alpha-helical regions with hydrophobic heptad repeats.[4] P62 assembles into a complex containing 3 addition proteins, p60, p54 and p45 , forming the p62 complex of ~235 kDa. Glycosylation appears to be involved in the assembly and disassembly of p62 into higher order complexes, and a serine/threonine rich linker region between Ser270 to Thr294 appear to be regulatory. The p62 complex is localized to both the nucleoplasmic and cytoplasmic sides of the pore complex and the relative diameter of p62 complex relative to the nuclear pore complex suggests it interacts in pore gating.

P62 appears to interact with mRNA during transport out of the nucleus. P62 also interacts with a nuclear transport factor (NTF2) protein that is involved in trafficking proteins between cytoplasm and nucleus. Another protein, importin (beta) binds to the helical rod section of p62, which also binds NTF2 suggesting the formation of a higher order gating complex. Karyopherin beta2 (transportin), a riboprotein transporter also interacts with p62. P62 also interacts with nucleoporin-93kDa, and when Nup98 is depleted p62 fails to assemble with nuclear pore complexes. Mutant pores could not dock/transport proteins with nuclear localization signals or M9 import signals.

Moscat and colleagues demonstrated that p62 activation in prostate and lung cancer epithelial cells had tumor-promoting effects. Cancers of the epithelial cells are called carcinomas, and about 85 percent of all cancers are carcinomas. These are highly significant observations since p62 activates another protein called mTOR which is a biological target of many ongoing clinical trials in cancer right now.

The initial hint that p62 in the stroma influences tumor growth came by analyzing more than 200 human prostate tumors with Gleason scores ranging from 2 to 10. Gleason scores are a numerical assignment given to prostate tumors based on pathology, with the highest scores (10 maximum) indicating that the cancer is very likely to spread. The research team found that p62 levels in the stroma were significantly lower in samples with the highest Gleason scores, suggesting a protective role for p62.

To understand how p62 works, the research team introduced prostate cancer cells and monitored tumor formation in normal mice, and mice genetically engineered to lack p62. The mice without p62, called p62 knockout (KO) mice, had larger prostate tumors compared to normal mice, supporting the notion that the absence of p62 in an organism promotes cancer growth.

The researchers went on to show that p62 KO mice had increased levels of IL-6, a pro-inflammatory cytokine (a signaling molecule) that enhances tumor cell proliferation and inhibits cell death. And, the genetic events that linked p62 depletion to increased levels of IL-6 in mice were mirrored in humans.

References:

1-Medical news today  July 07.2014

2- Nucleoporin p62,Wikipedia, the free encyclopedia  June 01, 2014

3- p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway

Angeles Duran1, 2, 3,Ramars Amanchy2, 3, Juan F. Linares1, 2, 3, Jayashree Joshi2, Shadi Abu-Baker2, Aleksey Porollo2, Malene Hansen1, Jorge Moscat1, 2, Maria T. Diaz-Meco1, 2,Molecular cell  Volume 44, Issue 1, 7 October 2011

 

ارسال شده توسط دکتر محمد هزارخانی در ساعت 11:57 بعد از ظهر |
Mon 7 Jul 2014

Urology news  July 07.2014

Castillo V1, Valenzuela R1, Huidobro C2, Contreras HR1, Castellon EA1.

Cancer stem cells (CSCs) have the ability to self-renew and differentiate to give rise to heterogeneous phenotype of the tumor cells. It is believed that these cells are involved in metastasis, recurrence and therapy resistance in various cancers.

CSCs have been identified in prostate cancer (PCa), one of the most diagnosed malignancies in men over the world, for which chemotherapy resistance is a major problem in the treatment of castration-resistant advanced stages. Molecular signatures, gene expression and functional features have been reported for PCa CSCs. Most data come from cell lines which may not represent the actual tumor. In the present work, a CSCs enriched population obtained from PCa explants was functionally characterized and analyzed for drug resistance.

Tumorsphere cultures positive for ABCG2 transporter, CD133, CD44, cytokeratins 5 and 18 (CK5 and CK18) and negatives for androgen receptor (AR) and prostate-specific antigen (PSA) showed higher clonogenic capacity, holoclone-forming ability, colony-forming capacity in soft agar and lower proliferative and apoptotic rate than control adherent cell cultures. Furthermore, exposing tumorsphere cultures to ABCG2 substrate drugs resulted in a high survival rate compared with control PCa cells. This high drug resistance was decreased using a selective inhibitor of ABCG2.

 According to these results, tumorspheres from PCa explants showed a functional stem phenotype and a marked drug resistance, probably mediated by high expression of the ABCG2 transporter, which might be considered as a suitable therapeutic target for CSCs.

Source: Int J Oncol. 2014 Sep;45(3):985-94. doi: 10.3892/ijo.2014.2529. Epub 2014 Jun 27.

ارسال شده توسط دکتر محمد هزارخانی در ساعت 11:7 بعد از ظهر |
Wed 2 Jul 2014

 

Edited by:Mohammad  Hezarkhani  MD,Urologist

Board-Certified of Urology,Tehran  University ,The Member  of  Iranian  Urological  Association

Madaen Hospital  Tehran Iran

Tehranclinic  Hospital Tehran Iran

Mohammad.hezarkhani@yahoo.com

www.Hezarkhani.blogfa.com  hosted in Washington DC, United States

July 01. 2014

Lysyl oxidase (LOX), also known as protein-lysine 6-oxidase, is a protein that, in humans, is encoded by the LOX gene. Its inhibition can cause lathyrism, but, at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous.Lysyl oxidase (LOX) is a multifunctional protein required for normal collagen and elastin biosynthesis and maturation. In addition, LOX has complex roles in cancer in which the lysyl oxidase propeptide (LOX-PP) domain of secreted pro-LOX has tumor-suppressor activity, while the active enzyme promotes metastasis.

Lysyl oxidase is an extracellular copper enzyme that catalyzes formation of aldehydes from lysine residues in collagen and elastin precursors. These aldehydes are highly reactive, and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in cross-linking collagen and elastin, which is essential for stabilization of collagen fibrils and for the integrity and elasticity of mature elastin.

Complex cross-links are formed in collagen (pyridinolines derived from three lysine residues) and in elastin (desmosines derived from four lysine residues) that differ in structure.

The importance of lysyl oxidase-derived cross-linking was established from animal studies in which lysyl oxidase was inhibited either by nutritional copper-deficiency or by supplementation of diets with β-aminopropionitrile (BAPN), an inhibitor of lysyl oxidase. This resulted in lathyrism, characterized by poor bone formation and strength, hyperextensible skin, weak ligaments, and increased occurrence of aortic aneurysms. These abnormalities correlated well with decreased cross-linking of collagen and elastin.

Developmentally, reduced lysyl oxidase levels have been implicated in Menkes disease and Occipital horn syndrome, two X-linked recessive disorders characterized by a mutation in a gene for copper transportation. Thus, not only is LOX crucial to cardiovascular development, it is thought to play a major role in connective tissue development and may also be important in neurological function.

Lysyl oxidase has also proven crucial to the development of the respiratory system and the skin, as collagen and elastin represent 50-60% of the composition of the lung, and 75% of the skin. In LOX double knockout models (Lox -/-), function of LOX was reduced by up to 80%, and the phenotype of the lungs resembles those of human patients with emphysema and dilated distal airways.

Finally, lysyl oxidase plays a crucial role in the commitment step of adipocyte, or fat cell, formation from pluripotent stem cells during development. Its absence may lead to defects in the transforming growth factor beta superfamily of proteins, which control cell growth and differentiation.

Secreted LOX is responsible for the invasive properties of hypoxic cancer cells through focal adhesion kinase activity and cell-to-matrix adhesion. LOX may be required to create a niche permissive for metastatic growth and, thus, may be required for hypoxia-induced metastasis. In fact, recent research has shown overexpression of LOX as crucial to promoting tumor growth and metastasis in several cancers, including breast cancer, melanoma, non-small cell lung cancer, and colorectal cancer.

Lysyl oxidase has been newly implicated in tumor angiogenesis, or blood vessel formation, both in vivo and in vitro. Subcutaneous tumor-derived LOX was shown to increase vascular endothelial growth factor (VEGF) expression and secretion, which then promotes angiogenesis by phosphorylation of protein kinase B, or Akt, through platelet-derived growth factor receptor β (PDGFRB). High levels of LOX were associated with high blood vessel density in patient samples. Clinically relevant LOX inhibitors may help slow cancer progression by downregulating crucial growth factors that promote solid tumor progression.

In prostate cancer cell lines, recombinant LOX-PP (rLOX-PP) inhibits the growth of PC3 cells in vitro by mechanisms that were not characterized, while in DU145 cells rLOX-PP targeted fibroblast growth factor signaling.

Because rLOX-PP can enhance effects of a genotoxic chemotherapeutic on breast cancer cell apoptosis, researchers reasoned that rLOX-PP could target DNA repair pathways typically elevated in cancer. The researchers demonstrate for the first time that rLOX-PP inhibits prostate xenograft growth in vivo and that activating phosphorylations of the key DNA repair molecules ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) are inhibited by rLOX-PP expression in vivo.

In addition, in vitro studies showed that rLOX-PP inhibits radiation-induced activating phosphorylations of ATM and CHK2 and that exogenously added rLOX-PP protein can localize to the nucleus in both DU145 and PC3 cells. rLOX-PP pull-down studies resulted in detection of a protein complex with the nuclear DNA repair regulator MRE11 in both cell lines, and rLOX-PP localized to radiation-induced nuclear DNA repair foci. Finally, rLOX-PP was shown to sensitize both DU145 and PC3 cells to radiation-induced cell death determined in colony-formation assays.

These data provide evidence that rLOX-PP has a nuclear mechanism of action in which it directly interacts with DNA repair proteins to sensitize prostate cancer cells to the effects of ionizing radiation.

References:

1-Effects of tumor-suppressor lysyl oxidase propeptide on prostate cancer xenograft growth and its direct interactions with DNA repair pathways- M V Bais, G B Ozdener, G E Sonenshein and P C Trackman/ Oncogene 0, (2 June 2014) | doi:10.1038/onc.2014.147

2-Lysyl oxidase, Wikipedia, the free encyclopedia     24 March 2014

ارسال شده توسط دکتر محمد هزارخانی در ساعت 0:4 قبل از ظهر |