BACKGROUND Less than 0.5%of intravenously injected drugs reach tumors,contributing to side effects.To limit damage to healthy cells,various delivery vectors have been formulated;yet,previously developed vectors suffer...BACKGROUND Less than 0.5%of intravenously injected drugs reach tumors,contributing to side effects.To limit damage to healthy cells,various delivery vectors have been formulated;yet,previously developed vectors suffer from poor penetration into solid tumors.This issue was resolved by the discovery of HN-1 peptide isolated via biopanning a phage-display library.HN-1 targets human head and neck squamous cell carcinoma(HNSCC)(breast,thyroid;potentially lung,cervix,uterine,colon cancer),translocates across the cell membrane,and efficiently infiltrates solid tumors.HN-1 peptide has been conjugated to various anticancer drugs and imaging agents though the identity of its receptor remained enigmatic.AIM To decipher the clues that pointed to retinoblastoma(Rb)-regulated discoidindomain receptor 1 as the putative receptor for HN-1 is described.METHODS HN-1 peptide was synthesized and purified using reverse-phase highperformance liquid chromatography and gel electrophoresis.The predicted mass was confirmed by mass spectroscopy.To image the 3-dimensional structure of HN-1 peptide,PyMOL was used.Molecular modeling was also performed with PEP-FOLD3 software via RPBS bioinformatics web portal(INSERM,France).The immunohistochemistry results of discoidin domain receptor 1(DDR1)protein were obtained from the publicly accessible database in the Human Protein Atlas portal,which contained the images of immunohistochemically labeled human cancers and the corresponding normal tissues.RESULTS The clues that led to DDR1 involved in metastasis as the putative receptor mediating HN-1 endocytosis are the following:(1)HN-1 is internalized in phosphate-buffered saline and its uptake is competitively inhibited;(2)HN-1(TSPLNIHNGQKL)exhibits similarity with a stretch of amino acids in alpha5 beta3 integrin(KLLITIHDRKEF).Aside from two identical residues(Ile-His)in the middle,the overall distribution of polar and nonpolar residues throughout the sequences is nearly identical.As HN-1 sequence lacks the Arg-Gly-Asp motif recognized by integrins,HN-1 may interact with an"integrin-like"molecule.The tertiary structure of both peptides showed similarity at the 3-dimensional level;(3)HN-1 is internalized by attached cells but not by suspended cells.As culture plates are typically coated with collagen,collagen-binding receptor(expressed by adherent but not suspended cells)may represent the receptor for HN-1;(4)DDR1 is highly expressed in head and neck cancer(or breast cancer)targeted by HN-1;(5)Upon activation by collagen,DDR1 becomes internalized and compartmentalized in endosomes consistent with the determination of’energy-dependent clathrin-mediated endocytosis’as the HN-1 entry route and the identification of HN-1 entrapped vesicles as endosomes;and(6)DDR1 is essential for the development of mammary glands consistent with the common embryonic lineage rationale used to identify breast cancer as an additional target of HN-1.In summary,collagenactivated tyrosine kinase receptor DDR1 overexpressed in HNSCC assumes a critical role in metastasis.Further studies are warranted to assess HN-1 peptide’s interaction with DDR1 and the therapeutic potential of treating metastatic cancer.Additionally,advances in delivery(conformation,endocytic mechanism,repertoire of targeted cancers of HN-1 peptide),tracking(HN-1 conjugated imaging agents),and activity(HN-1 conjugated therapeutic agents)are described.CONCLUSION The discovery of DDR1 as HN-1 peptide’s putative receptor represents a significant advance as it enables identification of metastatic cancers or clinical application of previously developed therapeutics to block metastasis.展开更多
Despite significant discoveries in basic cancer research and improvements in treatment options and clinical outcomes,cancer remains a major public health concern worldwide.Today,the main focus of cancer research is the...Despite significant discoveries in basic cancer research and improvements in treatment options and clinical outcomes,cancer remains a major public health concern worldwide.Today,the main focus of cancer research is the signaling pathways that are crucial for cell survival,cell proliferation,and cell migration.The aberrant expression of proteins involved in these signaling pathways often leads to abnormal cell growth,cell metastasis,and invasion of healthy tis-sues.One such protein is discoidin domain receptor 1(DDR1)which belongs to the family of receptor tyrosine kinases(RTKs)and is activated upon collagen binding,as a result,downstream signaling pathways are stimulated which are responsible for cell survival,cell growth,adhesion,extracellular matrix remodeling,and cell migration.DDR1 is found to have abnormally elevated expression in various solid tumors,implying a critical role in cancer progression.Tradi-tional cancer treatment involves the use of cytotoxic drugs,chemotherapy,radiotherapy,and surgery,which do not pro-vide long-term survival and often result in cancer recurrence.Numerous small-molecule kinase inhibitors have been synthesized against RTKs including DDR1 and have been highly efficacious in tumor reduction.More recently,targeting the DDR1 extracellular domain(ECD)has garnered much attention from researchers,as inhibiting the DDR1-collagen binding has been attributed to maximizing the likelihood of the combined cytotoxic effect of both immune cells and tar-geted drugs.This review focuses on the structure,function,activation,and signaling partners of DDR1,its role in different solid tumors,andfinally discusses about designing more DDR1 non-kinase inhibitors as promising therapeutic strategies against DDR1-driven tumors.展开更多
文摘BACKGROUND Less than 0.5%of intravenously injected drugs reach tumors,contributing to side effects.To limit damage to healthy cells,various delivery vectors have been formulated;yet,previously developed vectors suffer from poor penetration into solid tumors.This issue was resolved by the discovery of HN-1 peptide isolated via biopanning a phage-display library.HN-1 targets human head and neck squamous cell carcinoma(HNSCC)(breast,thyroid;potentially lung,cervix,uterine,colon cancer),translocates across the cell membrane,and efficiently infiltrates solid tumors.HN-1 peptide has been conjugated to various anticancer drugs and imaging agents though the identity of its receptor remained enigmatic.AIM To decipher the clues that pointed to retinoblastoma(Rb)-regulated discoidindomain receptor 1 as the putative receptor for HN-1 is described.METHODS HN-1 peptide was synthesized and purified using reverse-phase highperformance liquid chromatography and gel electrophoresis.The predicted mass was confirmed by mass spectroscopy.To image the 3-dimensional structure of HN-1 peptide,PyMOL was used.Molecular modeling was also performed with PEP-FOLD3 software via RPBS bioinformatics web portal(INSERM,France).The immunohistochemistry results of discoidin domain receptor 1(DDR1)protein were obtained from the publicly accessible database in the Human Protein Atlas portal,which contained the images of immunohistochemically labeled human cancers and the corresponding normal tissues.RESULTS The clues that led to DDR1 involved in metastasis as the putative receptor mediating HN-1 endocytosis are the following:(1)HN-1 is internalized in phosphate-buffered saline and its uptake is competitively inhibited;(2)HN-1(TSPLNIHNGQKL)exhibits similarity with a stretch of amino acids in alpha5 beta3 integrin(KLLITIHDRKEF).Aside from two identical residues(Ile-His)in the middle,the overall distribution of polar and nonpolar residues throughout the sequences is nearly identical.As HN-1 sequence lacks the Arg-Gly-Asp motif recognized by integrins,HN-1 may interact with an"integrin-like"molecule.The tertiary structure of both peptides showed similarity at the 3-dimensional level;(3)HN-1 is internalized by attached cells but not by suspended cells.As culture plates are typically coated with collagen,collagen-binding receptor(expressed by adherent but not suspended cells)may represent the receptor for HN-1;(4)DDR1 is highly expressed in head and neck cancer(or breast cancer)targeted by HN-1;(5)Upon activation by collagen,DDR1 becomes internalized and compartmentalized in endosomes consistent with the determination of’energy-dependent clathrin-mediated endocytosis’as the HN-1 entry route and the identification of HN-1 entrapped vesicles as endosomes;and(6)DDR1 is essential for the development of mammary glands consistent with the common embryonic lineage rationale used to identify breast cancer as an additional target of HN-1.In summary,collagenactivated tyrosine kinase receptor DDR1 overexpressed in HNSCC assumes a critical role in metastasis.Further studies are warranted to assess HN-1 peptide’s interaction with DDR1 and the therapeutic potential of treating metastatic cancer.Additionally,advances in delivery(conformation,endocytic mechanism,repertoire of targeted cancers of HN-1 peptide),tracking(HN-1 conjugated imaging agents),and activity(HN-1 conjugated therapeutic agents)are described.CONCLUSION The discovery of DDR1 as HN-1 peptide’s putative receptor represents a significant advance as it enables identification of metastatic cancers or clinical application of previously developed therapeutics to block metastasis.
基金T.J.is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0490000)S.B.and S.M.M.M.are supported by Chinese Academy of Sciences-The Alliance of International Science Organizations for Young Talents+1 种基金W.Z.is supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0490000)P.Z.is supported by the opening project of National&Local Joint Engineering Research Center of Deep Processing Technology for Aquatic Products.
文摘Despite significant discoveries in basic cancer research and improvements in treatment options and clinical outcomes,cancer remains a major public health concern worldwide.Today,the main focus of cancer research is the signaling pathways that are crucial for cell survival,cell proliferation,and cell migration.The aberrant expression of proteins involved in these signaling pathways often leads to abnormal cell growth,cell metastasis,and invasion of healthy tis-sues.One such protein is discoidin domain receptor 1(DDR1)which belongs to the family of receptor tyrosine kinases(RTKs)and is activated upon collagen binding,as a result,downstream signaling pathways are stimulated which are responsible for cell survival,cell growth,adhesion,extracellular matrix remodeling,and cell migration.DDR1 is found to have abnormally elevated expression in various solid tumors,implying a critical role in cancer progression.Tradi-tional cancer treatment involves the use of cytotoxic drugs,chemotherapy,radiotherapy,and surgery,which do not pro-vide long-term survival and often result in cancer recurrence.Numerous small-molecule kinase inhibitors have been synthesized against RTKs including DDR1 and have been highly efficacious in tumor reduction.More recently,targeting the DDR1 extracellular domain(ECD)has garnered much attention from researchers,as inhibiting the DDR1-collagen binding has been attributed to maximizing the likelihood of the combined cytotoxic effect of both immune cells and tar-geted drugs.This review focuses on the structure,function,activation,and signaling partners of DDR1,its role in different solid tumors,andfinally discusses about designing more DDR1 non-kinase inhibitors as promising therapeutic strategies against DDR1-driven tumors.
