Mucin-1

Last updated
MUC1
Protein MUC1 PDB 2acm.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases MUC1 , ADMCKD, ADMCKD1, CA 15-3, CD227, EMA, H23AG, KL-6, MAM6, MCD, MCKD, MCKD1, MUC-1, MUC-1/SEC, MUC-1/X, MUC1/ZD, PEM, PEMT, PUM, mucin 1, cell surface associated, ADTKD2, Ca15-3, Mucin-1
External IDs OMIM: 158340; HomoloGene: 136477; GeneCards: MUC1; OMA:MUC1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4582

n/a

Ensembl

ENSG00000185499

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UniProt

P15941
Q7Z551

n/a

RefSeq (mRNA)

n/a

RefSeq (protein)

n/a

Location (UCSC) Chr 1: 155.19 – 155.19 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Mucin-1(MUC-1) is a heterodimer transmembrane protein of the mucin family encoded in humans by the MUC1 gene. [3] [4] [5] It is cleaved into two chains: mucin-1 subunit alpha (MUC1-NT; MUC1-alpha) and mucin-1 subunit beta (MUC-CT; MUC1-beta). These subunits differ in size due to proteolytic cleavage of the translated precursor protein in the endoplasmic reticulum. [6] The larger subunit of MUC-1 is characterized by numerous O-glycosylated bonds and a terminal sialic acid, creating a net negative charge on MUC-1. [7] The smaller subunit contains a juxtamembrane region of the extracellular area, a transmembrane domain, and the cytoplasmic tail. [7] The extracellular domain of MUC-1 is composed of 20 identical amino acid tandem repeats (TR). [6] Each tandem repeat contains two serine and three threonine amino acid residues, providing five sites for potential O-glycosylation. [6] MUC-1 protein is estimated to weigh 120 to 225 kDA. [8]

The N-terminus of MUC-1 (MUC-1 N) contains variable number tandem repeats (VNTRs) of (PDTRPAPGSTAP PAHGVTSA). VNTR provides sites for glycosylation on proline, serine and threonine residues. [9] The peptide backbone exhibits glycosidic bonds between serine and threonine within MUC-1 N. [10] Within the cytoplasmic tail of MUC-1, multiple phosphorylation sites exist due to the presence of threonine, tyrosine and serine amino acid residues. [7] Alterations to the cytoplasmic tail may affect movement through the Golgi apparatus, thus affecting glycosylation of the tandem repeat domains of MUC-1. [6] The C-terminus of MUC-1 (MUC-1 C) is short—the majority of weight comes from N-glycosylation. [11] Research has shown that the C-terminus is linked to the development of inflammation and cancer. [12]

MUC-1 is located in the apical membrane on simple epithelial cell surfaces. These cells are found in the human kidney, gallbladder, stomach, lung, pancreas, mammary gland, and the female reproductive tract. [8] MUC-1 is removed from the membrane by endocytosis, [13] internalized, re-glycosylated and recycled to the cell membrane. [8] [5]

Function

O-glycosylation and N-glycosylation in MUC-1 contribute to the formation of mucin. [14] MUC-1 is a transcriptional coactivator involved in the activity and stabilization of enzymes and transcription of metabolic functions. MUC-1 regulates tyrosine kinase signaling receptors, which promote synthesis of biosynthetic intermediates used in cell growth. [14] In normal cells, the tandem repeats and cytoplasmic tail of MUC-1 are significant in the regulation and progression of metastatic cancer. Alterations to these areas have shown a propensity of metastasis and progression in comparison to unaltered MUC-1 domains. [6]

MUC-1 has many functions. MUC-1 is an inhibitor for cell-to-cell extracellular interactions for both normal and malignant cells. [8] The extracellular sperm protein–enterokinase–agarin (SEA) domain of MUC-1 contributes to a variety of functions including: inhibition of immune response, resistance to stimuli, and regulation of cell shedding. MUC-1 provides protection to the apical membrane to prevent rupture, as well as environmental and immune attack. [12] MUC-1 has been shown to repair epithelia through the activation of epigenetic reprogramming, epithelial-mesenchymal transition and self-renewing (stemness) in maintaining epithelial cell homeostasis. [15]

In cancer

MUC-1 is over expressed in many forms of cancer. [14] Given, MUC-1 is 10 times higher in cancer cells than normal cells, [16] an over expression of MUC-1 in cancer can be indicative of aggressive, metastatic cancer, having a low response to therapy and survival rate. [5] MUC-1 also exhibits altered glycosylation and aberrant surface distribution patterns in tumor cells. [6] Tumor related MUC-1 disrupts and inhibits cell-cell and cell-matrix interactions and adherence. [6] Inhibition of cellular interactions diminishes the adherence of immune effector cells to malignant cells, thereby creating an immunosuppressive effect. [6] MUC-1 in cancerous epithelial cells exhibits a loss of polarity. This loss of polarity creates incomplete carbohydrate side chains, allowing the formation of new abnormal side chains, thus increasing tumorigenesis. [10] In normal cells, MUC-1 is isolated to the apical surface of the cell. In cancer cells, over expression of MUC-1 is seen throughout the cell's nucleus, plasma membrane and cytoplasm. [5] In addition to the membranous isoform, an alternatively spliced mucin-1 is secreted extracellularly. [17]

Muc-1 in cancer cell activity Muc-1 in cancer vs normal cells.png
Muc-1 in cancer cell activity

MUC-1 in cancer is underglycosylated, causing interactions to form between MUC-1 core protein, transmembrane receptors, and extracellular components. [8] [5] The intercellular interaction between MUC-1 and the receptor ICAM-1 facilitates endothelial and epithelial cell interactions, allowing circulating cancer cells to adhere in the inner lining of blood vessels and thus migrate. [5] MUC-1 over expression is controlled through transcription changes, post-translational, and amplification modifications. In transcription, MUC-1 in cancer is regulated through STAT proteins, hormones, hypoxia, and growth factors. [5] MUC-1 plays a role in the increase of the autophagy of mitochondria, a process called mitophagy. An increase in mitophagy triggers the development and progression of cancer. [15]

MUC-1 cancer cell MUC-1 Cancer Cell.jpg
MUC-1 cancer cell

Breast cancer

MUC-1 is shown to be over expressed in 90% of triple-negative breast cancer (TNBC). MUC-1 C increases the progression of TNBC. MUC-1 C chronically activates pro-inflammatory pathways in cancer cells. [18] Triple-negative breast cancer stem cells rely on MUC-1 C for epithelial-mesenchymal transition, chromatin remodeling and epigenetic programming, which allow the cancer cells to avoid DNA damage and immune evasion. MUC-1 allows triple-negative breast cancer stem cells to engage in linear plasticity, a transition from one pathway into another, thus supporting the progression of TNBC. [18] Recent studies have shown changes of MUC-1 family antigences (CA 15-3, CA 27.29 and MCA) in saliva in breast cancer patients. Downregulated MUC1 was associated with HER2(+), high Ki-67 and G II-III. It showed a statistically significant increase in the cytokines VEGF, IL-1β, IL-2, IL-4, IL-10, and IL-18 against the background of reduced hormonal levels of estrogen and progesterone. The changes occurring locally in the oral cavity reflect complex biochemical shifts in the reactivity of the immune system of the entire body. This is manifested in the suppression of the anti-inflammatory activity of MUC1 due to proinflammatory cytokines that have passed the hematosalivary barrier and are activated by oncogenic processes occurring in breast cancer. The suppression of the anti-inflammatory activity also occurs because of a deficiency of estrogens and progesterone, inhibiting the expression of MUC1 on the epithelial cells of the oral mucosa. This cascade of biochemical reactions occurs due to the aggressive nature of the oncological process in HER2(+) breast cancer. [19]

Ovarian cancer

MUC-1 is over expressed in over 90% of all epithelial ovarian cancer. Currently, MUC-1 CT is being used to create therapies for ovarian cancer. Targeting MUC-1 CT to reduce expression has potential to control late-stage epithelial ovarian cancer. Since MUC-1 C does not contain a kinase or enzymatic function, targeting the protein's catalytic site is rendered useless. Research looking at breast cancer and MUC-1 showed promise in peptide blocking and disrupting MUC-1 CT interactions with specific effectors, decreasing proliferation, migration and invasion of metastatic breast cancer in vitro and inhibiting tumor growth and reoccurrence in mouse models. The results show promise for epithelial ovarian cancer therapies. [6]

Cancer therapy

Studies have shown MUC-1 over expression creates drug resistance during chemotherapy by altering glycolytic metabolism. [12] Over expression of MUC-1 decreases the apoptotic response to DNA damage, and increases anti-apoptotic Bcl-XL and PI3K/Akt pathways. [6] MUC-1 in tumor cells suppresses mitochondria from releasing apoptotic factors, creating resistance to genotoxic anticancer agents. [6] Cancer therapies are being developed to specifically target MUC-1 proteins, including peptide-based therapies, MUC-1 antibodies/conjugates, and MUC-1 vaccinations. [5] Peptide-based therapies develop peptides that target tumors and attack membranes with a cytotoxic effect. [20] Murine antibodies that are reactive with MUC-1 VNTR domain have been produced through immunization using milk fat globule membranes, isolated mucin preparations, and tumor cells. Developed MUC-1 monoclonal antibodies are used in diagnosis of cancer, and creation of target therapies. [6]

Related Research Articles

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

<span class="mw-page-title-main">Mucin-16</span> Mammalian protein found in Homo sapiens

Mucin-16(MUC-16) also known as Ovarian cancer-related tumor marker CA125 is a protein that in humans is encoded by the MUC16 gene. MUC-16 is a member of the mucin family glycoproteins. MUC-16 has found application as a tumor marker or biomarker that may be elevated in the blood of some patients with specific types of cancers, most notably ovarian cancer, or other conditions that are benign.

<span class="mw-page-title-main">Mucin</span> Glycoprotein

Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell signalling to forming chemical barriers. They often take an inhibitory role. Some mucins are associated with controlling mineralization, including nacre formation in mollusks, calcification in echinoderms and bone formation in vertebrates. They bind to pathogens as part of the immune system. Overexpression of the mucin proteins, especially MUC1, is associated with many types of cancer.

<span class="mw-page-title-main">Clusterin</span> Protein-coding gene in the species Homo sapiens

In humans, clusterin (CLU) is encoded by the CLU gene on chromosome 8. CLU is an extracellular molecular chaperone which binds to misfolded proteins in body fluids to neutralise their toxicity and mediate their cellular uptake by receptor-mediated endocytosis. Once internalised by cells, complexes between CLU and misfolded proteins are trafficked to lysosomes where they are degraded. CLU is involved in many diseases including neurodegenerative diseases, cancers, inflammatory diseases, and aging.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

Pemtumomab is a mouse monoclonal antibody used to treat cancer. The substance has affinity to various types of cancer, like ovarian cancer and peritoneal cancer, via the polymorphic epithelial mucin and delivers the radioisotope Yttrium-90 into the tumour. As of 2009, it is undergoing Phase III clinical trials.

<span class="mw-page-title-main">Galectin</span> Protein family binding to β-galactoside sugars

Galectins are a class of proteins that bind specifically to β-galactoside sugars, such as N-acetyllactosamine, which can be bound to proteins by either N-linked or O-linked glycosylation. They are also termed S-type lectins due to their dependency on disulphide bonds for stability and carbohydrate binding. There have been about 15 galectins discovered in mammals, encoded by the LGALS genes, which are numbered in a consecutive manner. Only galectin-1, -2, -3, -4, -7, -7B, -8, -9, -9B, 9C, -10, -12, -13, -14, and -16 have been identified in humans. Galectin-5 and -6 are found in rodents, whereas galectin-11 and -15 are uniquely found in sheep and goats. Members of the galectin family have also been discovered in other mammals, birds, amphibians, fish, nematodes, sponges, and some fungi. Unlike the majority of lectins they are not membrane bound, but soluble proteins with both intra- and extracellular functions. They have distinct but overlapping distributions but found primarily in the cytosol, nucleus, extracellular matrix or in circulation. Although many galectins must be secreted, they do not have a typical signal peptide required for classical secretion. The mechanism and reason for this non-classical secretion pathway is unknown.

<span class="mw-page-title-main">Mesothelin</span> Protein found in humans

Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<span class="mw-page-title-main">Heparin-binding EGF-like growth factor</span> Protein-coding gene in the species Homo sapiens

Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.

<span class="mw-page-title-main">Mucin short variant S1</span> Human protein

Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the MUC1 gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs. Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface. Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers. Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors.

<span class="mw-page-title-main">Mucin 4</span> Protein-coding gene in the species Homo sapiens

Mucin-4 (MUC-4) is a mucin protein that in humans is encoded by the MUC4 gene. Like other mucins, MUC-4 is a high-molecular weight glycoprotein.

An oncoantigen is a surface or soluble tumor antigen that supports tumor growth. A major problem of cancer immunotherapy is the selection of tumor cell variants that escape immune recognition. The notion of oncoantigen was set forth in the context of cancer immunoprevention to define a class of persistent tumor antigens not prone to escape from immune recognition.

<span class="mw-page-title-main">Epithelial cell adhesion molecule</span> Transmembrane glycoprotein

Epithelial cell adhesion molecule (EpCAM), also known as CD326 among other names, is a transmembrane glycoprotein mediating Ca2+-independent homotypic cell–cell adhesion in epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has oncogenic potential via its capacity to upregulate c-myc, e-fabp, and cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in tumorigenesis and metastasis of carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.

<span class="mw-page-title-main">RPN2</span> Protein-coding gene in the species Homo sapiens

Dolichyl-diphosphooligosaccharide—protein glycosyltransferase subunit 2, also called ribophorin ǁ is an enzyme that in humans is encoded by the RPN2 gene.

<span class="mw-page-title-main">EMP3</span> Protein-coding gene in the species Homo sapiens

Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule that is encoded by the myelin-related gene EMP3. EMP3 is a member of the peripheral myelin protein gene family 22-kDa (PMP22), which is mainly responsible for the formation of the sheath of compact myelin. Although the detailed functions and mechanisms of EMP3 still remain unclear, it is suggested that EMP3 is possibly epigenetically linked to certain carcinomas.

<span class="mw-page-title-main">Metastatic breast cancer</span> Type of cancer

Metastatic breast cancer, also referred to as metastases, advanced breast cancer, secondary tumors, secondaries or stage IV breast cancer, is a stage of breast cancer where the breast cancer cells have spread to distant sites beyond the axillary lymph nodes. There is no cure for metastatic breast cancer; there is no stage after IV.

O-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. O-glycosylation is a post-translational modification that occurs after the protein has been synthesised. In eukaryotes, it occurs in the endoplasmic reticulum, Golgi apparatus and occasionally in the cytoplasm; in prokaryotes, it occurs in the cytoplasm. Several different sugars can be added to the serine or threonine, and they affect the protein in different ways by changing protein stability and regulating protein activity. O-glycans, which are the sugars added to the serine or threonine, have numerous functions throughout the body, including trafficking of cells in the immune system, allowing recognition of foreign material, controlling cell metabolism and providing cartilage and tendon flexibility. Because of the many functions they have, changes in O-glycosylation are important in many diseases including cancer, diabetes and Alzheimer's. O-glycosylation occurs in all domains of life, including eukaryotes, archaea and a number of pathogenic bacteria including Burkholderia cenocepacia, Neisseria gonorrhoeae and Acinetobacter baumannii.

<span class="mw-page-title-main">Joyce Taylor-Papadimitriou</span> British molecular biologist and geneticist (born 1932)

Joyce Taylor-Papadimitriou FMedSci is a British molecular biologist and geneticist. She is Senior Fellow and Visiting Professor at King's College London specialising in the area of cellular, genetic and proteomic studies on patient breast tumour samples, and works within the Breast Cancer Biology Group. She was the first to identify that the action of interferon type 1 requires the synthesis of effector proteins.

hPG80 refers to the extracellular and oncogenic version of progastrin. This name first appeared in a scientific publication in January 2020. Until that date, scientific publications only mention 'progastrin', without necessarily explicitly specifying whether it is intracellular or extracellular in the tumor pathological setting.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000185499 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "UniProt". www.uniprot.org. Retrieved 7 November 2022.
  4. ↑ "MUC1 Gene - GeneCards | MUC1 Protein | MUC1 Antibody". www.genecards.org. Retrieved 7 November 2022.
  5. 1 2 3 4 5 6 7 8 Horm, Teresa M.; Schroeder, Joyce A. (2013-03-01). "MUC1 and metastatic cancer". Cell Adhesion & Migration. 7 (2): 187–198. doi:10.4161/cam.23131. ISSN   1933-6918. PMC   3954031 . PMID   23303343.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 Deng, Junli; Wang, Li; Chen, Hongmin; Li, Lei; Ma, Yiming; Ni, Jie; Li, Yong (2013-12-01). "The role of tumour-associated MUC1 in epithelial ovarian cancer metastasis and progression". Cancer and Metastasis Reviews. 32 (3): 535–551. doi: 10.1007/s10555-013-9423-y . ISSN   1573-7233. PMID   23609751. S2CID   254384521.
  7. 1 2 3 Wang, Honghe; Lillehoj, Erik P.; Kim, K. Chul (2004-08-20). "MUC1 tyrosine phosphorylation activates the extracellular signal-regulated kinase". Biochemical and Biophysical Research Communications. 321 (2): 448–454. doi:10.1016/j.bbrc.2004.06.167. ISSN   0006-291X. PMID   15358196.
  8. 1 2 3 4 5 Brayman M, Thathiah A, Carson DD (January 2004). "MUC1: a multifunctional cell surface component of reproductive tissue epithelia". Reproductive Biology and Endocrinology. 2: 4. doi: 10.1186/1477-7827-2-4 . PMC   320498 . PMID   14711375.
  9. ↑ Qing, Liangliang; Li, Qingchao; Dong, Zhilong (2022-11-01). "MUC1: An emerging target in cancer treatment and diagnosis". Bulletin du Cancer. 109 (11): 1202–1216. doi:10.1016/j.bulcan.2022.08.001. ISSN   0007-4551. PMID   36184332. S2CID   252649766.
  10. 1 2 Chen W, Zhang Z, Zhang S, Zhu P, Ko JK, Yung KK (June 2021). "MUC1: Structure, Function, and Clinic Application in Epithelial Cancers". International Journal of Molecular Sciences. 22 (12): 6567. doi: 10.3390/ijms22126567 . PMC   8234110 . PMID   34207342.
  11. ↑ Nath S, Mukherjee P (June 2014). "MUC1: a multifaceted oncoprotein with a key role in cancer progression". Trends in Molecular Medicine. 20 (6): 332–342. doi:10.1016/j.molmed.2014.02.007. PMC   5500204 . PMID   24667139.
  12. 1 2 3 Chen W, Zhang Z, Zhang S, Zhu P, Ko JK, Yung KK (June 2021). "MUC1: Structure, Function, and Clinic Application in Epithelial Cancers". International Journal of Molecular Sciences. 22 (12): 6567. doi: 10.3390/ijms22126567 . PMC   8234110 . PMID   34207342.
  13. ↑ Altschuler Y, Kinlough CL, Poland PA, Bruns JB, Apodaca G, Weisz OA, Hughey RP (2000). "Clathrin-mediated Endocytosis of MUC1 Is Modulated by Its Glycosylation State". Molecular Biology of the Cell. 11 (3): 819–831. doi: 10.1091/mbc.11.3.819 . PMC   14813 . PMID   10712502.
  14. 1 2 3 Mehla K, Singh PK (April 2014). "MUC1: a novel metabolic master regulator". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1845 (2): 126–135. doi:10.1016/j.bbcan.2014.01.001. PMC   4045475 . PMID   24418575.
  15. 1 2 Li Q, Chu Y, Li S, Yu L, Deng H, Liao C, et al. (October 2022). "The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization". Cell Death & Disease. 13 (10): 899. doi:10.1038/s41419-022-05345-z. PMC   9606306 . PMID   36289190.
  16. ↑ Bose M, Mukherjee P (November 2020). "Potential of Anti-MUC1 Antibodies as a Targeted Therapy for Gastrointestinal Cancers". Vaccines. 8 (4): 659. doi: 10.3390/vaccines8040659 . PMC   7712407 . PMID   33167508.
  17. ↑ Baruch A, Hartmann M, Yoeli M, Adereth Y, Greenstein S, Stadler Y, Skornik Y, Zaretsky J, Smorodinsky NI, Keydar I, Wreschner DH (1999). "The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein". Cancer Research. 59 (7): 1552–1561. PMID   10197628. S2CID   25997699.
  18. 1 2 Yamashita N, Kufe D (July 2022). "Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression". International Journal of Molecular Sciences. 23 (15): 8219. doi: 10.3390/ijms23158219 . PMC   9331006 . PMID   35897789.
  19. ↑ Dyachenko, Elena I.; Bel’skaya, Lyudmila V. (January 2024). "Salivary Transmembrane Mucins of the MUC1 Family (CA 15-3, CA 27.29, MCA) in Breast Cancer: The Effect of Human Epidermal Growth Factor Receptor 2 (HER2)". Cancers. 16 (20): 3461. doi: 10.3390/cancers16203461 . ISSN   2072-6694 . Retrieved 31 October 2024. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
  20. ↑ Boohaker, R. J.; Lee, M. W.; Vishnubhotla, P.; Perez, J. L. M.; Khaled, A. R. (2012). "The Use of Therapeutic Peptides to Target and to Kill Cancer Cells". Current Medicinal Chemistry. 19 (22): 3794–3804. doi:10.2174/092986712801661004. PMC   4537071 . PMID   22725698.
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