Cancer‐specific antigens expressed in the cell membrane have been used as targets for several molecular targeted strategies in the last 20 years with remarkable success. To develop more effective cancer treatments, novel targets and strategies for targeted therapies are needed. Here, we examined the cancer cell membrane‐resident “cis‐bimolecular complex” as a possible cancer target (cis‐bimolecular cancer target: BiCAT) using proximity proteomics, a technique that has attracted attention in the last 10 years. BiCAT were detected using a previously developed method termed the enzyme‐mediated activation of radical source (EMARS), to label the components proximal to a given cell membrane molecule. EMARS analysis identified some BiCAT, such as close homolog of L1 (CHL1), fibroblast growth factor 3 (FGFR3) and α2 integrin, which are commonly expressed in mouse primary lung cancer cells and human lung squamous cell carcinoma cells. Analysis of cancer specimens from 55 lung cancer patients revealed that CHL1 and α2 integrin were highly co–expressed in almost all cancer tissues compared with normal lung tissues. As an example of BiCAT application, in vitro simulation of effective drug combinations used for multiple drug treatment strategies was performed using reagents targeted to BiCAT molecules. The combination treatment based on BiCAT information moderately suppressed cancer cell proliferation compared with single administration, suggesting that the information about BiCAT in cancer cells is useful for the appropriate selection of the combination among molecular targeted reagents. Thus, BiCAT has the potential to contribute to several molecular targeted strategies in future.
Cancer‐specific antigens expressed in the cell membrane have been used as targets for several molecular targeted strategies in the last 20 years with remarkable success. To develop more effective cancer treatments, novel targets and strategies for targeted therapies are needed. Here, we examined the cancer cell membrane‐resident “cis‐bimolecular complex” as a possible cancer target (cis‐bimolecular cancer target: BiCAT) using proximity proteomics, a technique that has attracted attention in the last 10 years. BiCAT were detected using a previously developed method termed the enzyme‐mediated activation of radical source (EMARS), to label the components proximal to a given cell membrane molecule. EMARS analysis identified some BiCAT, such as close homolog of L1 (CHL1), fibroblast growth factor 3 (FGFR3) and α2 integrin, which are commonly expressed in mouse primary lung cancer cells and human lung squamous cell carcinoma cells. Analysis of cancer specimens from 55 lung cancer patients revealed that CHL1 and α2 integrin were highly co–expressed in almost all cancer tissues compared with normal lung tissues. As an example of BiCAT application, in vitro simulation of effective drug combinations used for multiple drug treatment strategies was performed using reagents targeted to BiCAT molecules. The combination treatment based on BiCAT information moderately suppressed cancer cell proliferation compared with single administration, suggesting that the information about BiCAT in cancer cells is useful for the appropriate selection of the combination among molecular targeted reagents. Thus, BiCAT has the potential to contribute to several molecular targeted strategies in future.
Extracellular vesicles (EVs) are
biomarkers and mediators of intercellular
communication. In biological samples, EVs are secreted by various
types of cells. The proteomic identification of proteins expressed
in EVs has potential to contribute to research and clinical applications,
particularly for cancer. In this study, the proximity-labeling method-based
proteomic approach was used for EV identification, labeling membrane
components proximal to a given molecule on the EV membrane surface.
Due to the small labeling range, proteins on the surface of the same
EVs are likely to be labeled by selecting a given EV surface antigen.
The protein group of cancer cell-secreted EV (cEV), which abundantly
expresses a close homologue of L1 (CHL1), was examined using a model
mouse for lung cancer (LC). cEV-expressed proteins were identified
by proteomic analysis of enzyme-mediated activation of radical sources
by comparing serum EVs from wild-type and LC mice. SLC4A1 was found
to be co-expressed in CHL1-expressing EVs, highlighting EVs expressing
both CHL1 and SLC4A1 as candidates for cEVs. Serum EVs expressing
both CHL1 and caspase 14 were significantly elevated in LC patients
compared with healthy individuals. Thus, the combination of proximity
labeling and proteomic analysis allows for effective EV identification.
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