“Tumstatin”的意思、由来-开放百科全书

Tumstatin is a 28 kDa fragment cleaved from collagen type IV There are two subsegments of the peptide that are active; T3 peptide and T7 peptide.^[4] The structure is very similar to that of endostatin, which is cleaved from collagen XVIII.^[5] The two proteins share 14% amino acid identity, making them very similar in structure.^[1] It has been proven to inhibit many types of cells, including bovine endothelial cells, HeLa cells, endothelial cells, and Human umbilical vein endothelial cells (HUVEC) cells.^[1]^[4]^[9]

Mechanism of action

The tumstatin fragment is cleaved by matrix metalloproteinase-9 (MMP) at the alpha chain on the collagen strand.^[2] Tumstatin interacts with the αvβ3 integrin found in the apoptosis pathway. There are two activation sites on the tumstatin fragment. One is at the N-terminus and is responsible for inhibiting angiogenesis. The other is at the C-terminus end and is primarily responsible for the proapoptotic action.^[6] Tumstatin inhibits the activation of FAK (Focal Adhesion Kinase), Phosphoinositide 3-kinase (PI3-kinase), protein kinase B (PKB/Akt), and mammalian target of rapamycin (mTOR). In addition to affecting these pathways, it also prevents the dissociation of eukaryotic initiation factor 4E protein (eIF4E) from 4Ebinding protein 1.^[7] These pathways are involved in cell proliferation, so tumstatin reacting with them results in changes in the amount of cell division that occurs.

Antiangiogenesis actions

Since tumstatin has been shown to reduce angiogenesis in tumors, there is great potential to use this knowledge as treatment for cancer. Tumstatin binds to the endothelium of the tumor and is thus able to affect tumor growth.^[8] By affecting the apoptotic pathway, tumstatin inhibits the proliferation of endothelial cells.^[1]^[9] Tumstatin is a cell-specific inhibitor for protein synthesis and therefore affects angiogenesis, which occurs at the protein synthesis level.^[7] It has been shown that the efficacy of tumstatin in reducing angiogenesis in tumors increases with tumor size (tumors larger than 500 mm³).^[8]

In addition to limiting the proliferation of endothelial cells, tumstatin also limits angiogenesis in melanoma cells.^[9]^[10] The 54-132 amino acid sequence of the tumstatin fragment binds both endothelial and melanoma cells but only inhibits endothelial cell proliferation which the 185-203 amino acid sequence also binds both and inhibits only melanoma proliferation.^[10] This is important in discovering the correct binding sites for different cells types and could help to make cancer therapies more cell-type specific.

One study showed that mice with a genetic deletion of the αvβ3 integrin showed accelerated tumor growth and that when tumstatin was replaced into the system, the tumor growth was disrupted and the tumor shrunk.^[11] It has also been shown that tumstatin has antiangiogenic properties in prostate cancer cells (PCa). PCa was introduced onto a Matrigel and treated with tumstatin, and the formation of new blood vessels as seen in the control did not occur with tumstatin.^[12] These studies suggest that tumstatin may be a viable treatment for many types of cancer, including but not limited to melanoma and prostate cancer.

Combination treatments involving tumstatin paired with another cancer-fighting drug could be extremely beneficial. One study combined treatments of tumstatin with bevacizumab, or Avastin. This was very successful in downregulating the proliferation of renal carcinoma cells in xenografts.^[8]

Proapoptotic actions

The second mechanism of action for tumstatin in combating cancer cells is to induce apoptosis. Apoptosis is induced through the same receptor as the antiangiogenic receptor, αvβ3. It has been shown to increase apoptosis in HUVEC cells as well as HeLa cells.^[1]^[9]

One study has been done to determine the exact pathway used by tumstatin to induce apoptosis. This revealed that the pathway occurs within the mitochondria. The study used HepG2 human liver carcinoma cells to test this, and found that tumstatin upregulated the expression of Caspase-9, Fas, Bax, Bid, and p53 while downregulating Bcl-2. The addition of tumstatin induced the release of cytochrome c by decreasing the mitochondrial membrane potential.^[13] These results show that the proapoptotic activation pathway for tumstatin occurs through mitochondrial regulation, and can aid in determining appropriate cancer treatments.

Role in other diseases

Since the mechanisms of both of these pathways are not unique to cancer, tumstatin’s regulation of angiogenesis and apoptosis has potential to treat other diseases affected by these pathways as well.

Diabetes

These findings suggest that tumstatin might be used as a treatment for diabetes by regulating the angiogenesis pathways.

Asthma

In patients with asthma, treatment with tumstatin may be beneficial. Type-IV collagen is present in the basement membrane within normal lungs, and this is reduced in asthmatic patients. There are also increased levels of MMP in the lungs of asthmatics. Since tumstatin is cleaved by MMP from the collagen in the basement membrane, it has been found that there are much lower levels of tumstatin in the airways of asthmatics than in normal patients.^[16] This could account for the increased angiogenesis and hyperresponsiveness of the airways. Increasing the levels of tumstatin in the airways would lead to decreased angiogenesis and therefore eased breathing.

See also

References

1. ^¹²³⁴{{cite journal |vauthors=Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R |title=Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by αVß3 and α5ß1 integrins |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=100 |issue=8 |pages=4766–71 |date=April 2003 |pmid=12682293 |pmc=153630 |doi=10.1073/pnas.0730882100 }}
2. ^¹http://www.copewithcytokines.de/cope.cgi?key=Tumstatin{{full citation needed|date=September 2018}}
3. ^{{Cite web | url=http://www.merriam-webster.com/dictionary/angiogenesis. | title=Definition of ANGIOGENESIS}}
4. ^¹http://www.phoenixpeptide.com/catalog/pnxfoget.php?id=pnxnews_000000444&title=Compound&sum=Function.
5. ^{{cite journal |author=Folkman J |title=Tumor suppression by p53 is mediated in part by the antiangiogenic activity of endostatin and tumstatin |journal=Sci. STKE |volume=2006 |issue=354 |pages=pe35 |date=September 2006 |pmid=17003465 |doi=10.1126/stke.3542006pe35 }}
6. ^{{cite book |author1=Stewart, David Kenney |author2=Stillman, Bruce |title=Molecular approaches to controlling cancer |publisher=Cold Spring Harbor Laboratory Press |location=Plainview, N.Y |date=30 August 2005 |isbn=978-0-87969-773-0 }}
7. ^¹{{cite journal |vauthors=Maeshima Y, Sudhakar A, Lively JC, etal |title=Tumstatin, an endothelial cell-specific inhibitor of protein synthesis |journal=Science |volume=295 |issue=5552 |pages=140–3 |date=January 2002 |pmid=11778052 |doi=10.1126/science.1065298 }}
8. ^¹²{{cite journal |vauthors=Eikesdal HP, Sugimoto H, Birrane G, etal |title=Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=105 |issue=39 |pages=15040–5 |date=September 2008 |pmid=18818312 |pmc=2567489 |doi=10.1073/pnas.0807055105 }}
9. ^¹²³{{cite conference |author1=Wang Shu-jing |author2=Liu Xing-han |author3=Ji Yu-bin |author4=Chen Ning |title=The Effect of Tumstatin Anti-tumor Peptide on Proliferation and Apoptosis of Different Cells |date=6–8 July 2007 |booktitle=Bioinformatics and Biomedical Engineering, 2007. ICBBE 2007 |publisher=IEEE |pages=122–5 |isbn=1-4244-1120-3 |url=http://ieeexplore.ieee.org/search/freesrchabstract.jsp?tp=&arnumber=4272519 |doi=10.1109/ICBBE.2007.35 }}
10. ^¹{{cite journal |vauthors=Maeshima Y, Colorado PC, Kalluri R |title=Two RGD-independent alpha vbeta 3 integrin binding sites on tumstatin regulate distinct anti-tumor properties |journal=J. Biol. Chem. |volume=275 |issue=31 |pages=23745–50 |date=August 2000 |pmid=10837460 |doi=10.1074/jbc.C000186200 }}
11. ^{{cite journal |vauthors=Hamano Y, Zeisberg M, Sugimoto H, etal |title=Physiological levels of tumstatin, a fragment of collagen IV α3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via αVß3 integrin |journal=Cancer Cell |volume=3 |issue=6 |pages=589–601 |date=June 2003 |pmid=12842087 |pmc=2775452 |doi=10.1016/S1535-6108(03)00133-8}}
12. ^{{cite journal |vauthors=Nyberg P, Xie L, Kalluri R |title=Endogenous inhibitors of angiogenesis |journal=Cancer Res. |volume=65 |issue=10 |pages=3967–79 |date=May 2005 |pmid=15899784 |doi=10.1158/0008-5472.CAN-04-2427 }}
13. ^{{cite journal |vauthors=Liu Y, Li J, Xu H, Zhang Y, Liu Y, Liu X |title=Mitochondria-mediated tumstatin peptide-induced HepG2 cell apoptosis |journal=Int. J. Mol. Med. |volume=24 |issue=5 |pages=653–9 |date=November 2009 |pmid=19787199 |doi=10.3892/ijmm_00000276}}
14. ^{{EMedicine|article|238946|Diabetic Nephropathy}}
15. ^{{cite journal |vauthors=Yamamoto Y, Maeshima Y, Kitayama H, etal |title=Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy |journal=Diabetes |volume=53 |issue=7 |pages=1831–40 |date=July 2004 |pmid=15220208 |doi=10.2337/diabetes.53.7.1831}}
16. ^{{cite journal |vauthors=Burgess JK, Boustany S, Moir LM, etal |title=Reduction of tumstatin in asthmatic airways contributes to angiogenesis, inflammation, and hyperresponsiveness |journal=Am. J. Respir. Crit. Care Med. |volume=181 |issue=2 |pages=106–15 |date=January 2010 |pmid=19875687 |doi=10.1164/rccm.200904-0631OC }}

Structure and Function