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Recently, Nature Communications published a paper entitled "The blood proteome of imminent lung cancer diagnosis". Using a high-throughput proteomics approach, researchers at Harvard Medical School screened blood samples from smokers for proteins associated with the risk of an imminent lung cancer diagnosis, including CEACAM5, MUC-16, IL6, CXCL9, CXCL13, and CDCP1 [1].
CDCP1 is a novel tumor therapy target. Multiple drugs are being developed against it, mainly for solid tumors with high CDCP1 expression. These drugs can inhibit the migration and invasion of tumor cells while protecting normal cells, especially hematopoietic stem cells. Thus, CDCP1, as an important regulator of the oncogenic signaling pathway, holds immense potential for drug development, offering new opportunities for tumor patients.
2. How's the Mechanism Actions of CDCP1 in Tumors?
CUB-domain containing protein 1 (CDCP1), also called CD318, SIMA135, gp140, or TRASK, is a type I transmembrane glycoprotein. Discovered via cDNA microarray technology by Scherlmostageerm et al. in 2001, it's a novel human tumor-associated gene. CDCP1's full form includes 836 amino acids, with a 29-amino acid signal peptide, extracellular, transmembrane, and cytoplasmic domains. The extracellular part features three CUB-like domains, likely for cellular adhesion or interacting with the extracellular matrix. CDCP1 can be hydrolyzed by proteases like ADAM9, forming homodimers. This event induces tyrosine phosphorylation by proteins like Src and PKCδ, thereby initiating metastatic activity (Figure 1) [2-4].
CDCP1 expression appears in vivo in various tissue stem cells and precursors, including hematopoietic stem cell progenitors and neural progenitor cells. Recent research links dysregulated CDCP1 expression to tumorigenesis, driving migration and invasion in malignancies, a vital role in tumor development. Furthermore, CDCP1's impact extends to tumor development through regulating intra-tumor cytokines. This role affects the tumor immune response by governing cytokine activity, including IL-2 and HLA-B19, ultimately impacting treatment outcomes. CDCP1 is now a prominent target in anti-tumor drug research [5-6].
Figure 1. CDCP1 structure [2]
Currently, the mechanism of tyrosine phosphorylation interaction between SFKs, PKCδ and CDCP1 is receiving attention. Relevant studies have shown that CDCP1 interact with SFKs, PKCδ, and PKCδ by regulating downstream complex amino acid phosphorylation signaling pathways such as PI3K/Akt, PKC5, SRC and ERK/MAPK etc., play important roles in promoting tumor invasion and metastasis (Figure 2) [7].
In prostate cancer cells, CDCP1 gene expression is usually suppressed by androgens, maintaining low levels. Yet, androgen-independent prostate cancer sees elevated CDCP1 due to androgen deprivation. This activates Akt and SRC/MAPK pathways, possibly driving CRPC progression [8]. Additionally, CDCP1 deletion regulates CDK5, impacting integrin β1/ITGB1 expression in non-adherent cells and promoting vascular proliferation in advanced prostate cancer patients [9].
In colorectal cancer, CDCP1 boosts Wnt signaling via β-catenin and E-cadherin translocation [10]. In triple-negative breast cancer, PDGF-BB activates PDGFRβ, triggering ERK1/2 and raising CDCP1 expression [11]. In lung cancer, ADAM9 activates EGFR and decreases miR-1, upregulating CDCP1 and promoting progression [12]. Kidney cancer shows HIF-2α overexpression fueling CDCP1 and tyrosine phosphorylation, suggesting CDCP1 as a metastatic cancer biomarker and target [13].
Figure 2. CDCP1 associated signaling pathway in tumors [7]
Prostate Cancer (PCa) is a prevalent male tumor. Androgen Deprivation Therapy (ADT) effectively manages advanced prostate cancer and prevents recurrence by either suppressing androgen production or blocking Androgen Receptor (AR) signaling. Yet, drug resistance emerges in most patients, leading to androgen-independent and therapy-resistant Prostate Cancer (CRPC). Consequently, CRPC remains a formidable clinical challenge [14].
CDCP1 is highly expressed in AR-negative CRPC cells, correlating positively with BRD4 and CBP/p300. These are vital regulators upstream in the PCa cell pathway. Targeting them lowers oncogenic markers like EGFR, c-Myc, ERK/p-ERK、Akt/p-Akt and more. BRD4 and CBP/p300 bind CDCP1 gene regions, impacting H3K27ac levels and transcription. Dual inhibitor NEO2734 effectively curbs CDCP1 expression and hampers growth in AR-positive and AR-negative CRPC cells (Figure 3) [15]. Also, CDCP1, in synergy with PTEN deficiency, promotes metastatic prostate cancer development [16].
Figure 3. Targeting CDCP1 via dual inhibitor curbs CRPC development [15]
CDCP1 is a molecular marker associated with the prognosis of colorectal cancer. Patients with its high expression have shorter overall and disease-free survival than those with low expression. In in vitro experiments, silencing the expression of CDCP1 could effectively inhibit the migration and invasion ability of HCT116 cells, suggesting that overexpression of CDCP1 promotes the metastasis and invasion of cancer cells. In addition, RHO-associated frizzled helix-binding protein kinase 1 (ROCK1) is an important downstream signaling molecule in the regulation of migration and invasion by CDCP1 [17].
Lung cancer is one of the common malignant tumors, of which non-small cell lung cancer (NSCLC) accounts for more than 70-80% of lung cancers. For EGFR mutation-positive NSCLC patients treated with EGFR TKI, researchers found that CDCP1 is an independent negative prognostic factor affecting patients' Progression-Free Survival (PFS) and Overall Survival (OS) [18-19]. A related study found that high levels of ADAM9 and CDCP1 in clinical specimens of lung cancer patients were associated with high mortality. In addition, ADAM9 activates the EGFR signaling pathway and enhances CDCP1 expression to promote lung cancer [12, 20].
In pancreatic cancer, CDCP1 shows high expression. AHCC, derived from mycorrhizal plants, can hinder pancreatic cancer's malignancy by lowering CDCP1 expression. Meanwhile, CDCP1's extracellular CUB2 domain allows it to form homotypic complexes by binding to another CDCP1 molecule. These complexes activate SFK signaling, propelling cancer cell migration. To counter this, researchers used a recombinant CUB2 domain protein (rMBPCUB2) tagged with maltose-binding protein, disrupting CDCP1 binding and reducing homotypic complexes. This hints that obstructing CDCP1's homotypic binding site could be a potential strategy for CDCP1-related tumor treatment [21].
In breast cancer, CDCP1 is a key player in the HER2 signaling pathway, crucial for migration and tumor formation when both are overexpressed [22]. For triple-negative breast cancer (TNBC), FBXL14, a ubiquitin ligase, impacts CDCP1 levels. FBXL14 promotes CDCP1's ubiquitination and proteasomal degradation, curbing its stability. This, in turn, affects the expression of metastasis-related genes involving CDCP1 [23]. This study unveils a mechanism influencing CDCP1 stability, proving it a more accurate prognosis predictor in breast cancer than gene expression levels.
CDCP1 is also highly expressed in a variety of other cancers, such as laryngeal cancer [24], cervical cancer [25], renal cancer [13], hepatocellular carcinoma [26], chronic myeloid leukemia (CML) [27], and acute myeloid leukemia (AML) [28-29]. Taking laryngeal cancer as an example, a study detected MMP-9 in laryngeal cancer tissues and paracancerous tissues.They also examined MMP-9, CDCP1 and NLK levels in these tissues. Surprisingly, all three proteins were busier in the laryngeal cancer tissues, especially NLK. NLK acts a bit like a conductor for the cells' signals, directing their actions [24].
Besides, know-down of NLK expression in laryngeal cancer cells Hep-2 reduced the proliferation and invasion ability of cells and increased Caspase-3 activity. Caspase-3 is an apoptosis-related enzyme. Meanwhile, interfering with NLK expression also decreased the expression of MMP-9 and CDCP1. These results suggest that NLK may be involved in the proliferation, apoptosis, and invasion process of laryngeal cancer cells by affecting the expression of MMP-9 and CDCP1 [24].
Several global companies, like Chiome Bioscience, Inc., UCSF Innovation Ventures, Miltenyi Biotec, Inc., and Heidelberg Pharma Research GmbH, are investing in CDCP1 drug research. They're working on monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR T-cell therapies. Chiome Bioscience, Inc. stands out with its anti-CDCP1 antibody-drug conjugate (h14A043-ATAC), showing promise against solid cancers in preclinical stages. Their CDCP1 monoclonal antibody inhibitor (PCDC) is also in preclinical trials. All in all, these initiatives mark a significant leap towards realizing the potential of CDCP1-targeted therapies in various tumors.
CUB-domain containing protein 1 (CDCP1) is a cell surface glycoprotein, which is dysregulated in several cancers with potential as a target for cancer treatment. Backed by investments and collaborative research efforts from global leaders like Chiome Bioscience, Inc, CDCP1 presents a potential breakthrough against solid cancers in preclinical stages. More research is conducted to determine potent of targeting CDCP1 or associated proteins. Currently, CDCP1 is served as not only a marker for cancer, but also a cancer drug target!
To fully support researchers and pharmaceutical companies in their research on CDCP1 in autoimmune diseases, tumors, or other diseases, CUSABIO presents CDCP1 active proteins & antibodies to support your research on the mechanism of CDCP1 or its potential clinical value.
CDCP1 protein
● Recombinant Human CUB domain-containing protein 1(CDCP1),partial (Active) (Code: CSB-MP884474HU)
Purity was greater than 95% as determined by SDS-PAGE.
Immobilized Human CDCP1 at 2μg/mL can bind Anti-CDCP1 recombinant antibody (CSB-RA884474MA1HU), the EC50 is 0.2943-0.4429 ng/mL.
● Recombinant Mouse CUB domain-containing protein 1(Cdcp1),partial (Active) (Code: CSB-MP719456MO)
Purity was greater than 95% as determined by SDS-PAGE.
Immobilized Mouse Cdcp1 at 2 μg/mL can bind Anti-CDCP1 recombinant antibody (CSB-RA884474MA1HU), the EC50 is 0.6397-0.8369 ng/mL.
Purity was greater than 95% as determined by SDS-PAGE.
Immobilized Macaca fascicularis CDCP1 at 2μg/mL can bind Anti-CDCP1 recombinant antibody (CSB-RA884474MA1HU)，the EC50 is 1.861-2.330 ng/mL.
References
[1] Albanes, Demetrius, et al. "The blood proteome of imminent lung cancer diagnosis." Nature Communications 14.1 (2023).
[2] Wortmann, Andreas, et al. "The cell surface glycoprotein CDCP1 in cancer-insights, opportunities, and challenges." IUBMB life 61.7 ( 2009): 723-730.
[3] Murakami, Yuichi, et al. "AXL/CDCP1/SRC axis confers acquired resistance to osimertinib in lung cancer." Scientific Reports 12.1 (2022): 8983.
[4] Uekita, Takamasa, and Ryuichi Sakai. "Roles of CUB domain-containing protein 1 signaling in cancer invasion and metastasis." Cancer science 102.11 (2011): 1943-1948.
[5] Qi, Xiao, et al. "CDCP1: A promising diagnostic biomarker and therapeutic target for human cancer." Life Sciences 301 (2022): 120600.
[6] Hooper, John D., et al. "Subtractive immunization using highly metastatic human tumor cells identifies SIMA135/CDCP1, a 135 kDa cell surface phosphorylated glycoprotein antigen." Oncogene 22.12 (2003): 1783-1794.
[7] Casar, B., et al. "In vivo cleaved CDCP1 promotes early tumor dissemination via complexing with activated β1 integrin and induction of FAK/PI3K/Akt motility signaling." Oncogene 33.2 (2014): 255-268.
[8] Alajati, Abdullah, et al. "CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo." the Journal of clinical investigation 130.5 (2020): 2435-2450.
[9] Pollan, Sara G., et al. "Regulation of inside-out β1-integrin activation by CDCP1." Oncogene 37.21 (2018): 2817-2836.
[10] He, Yaowu, et al. "CDCP1 enhances Wnt signaling in colorectal cancer promoting nuclear localization of β-catenin and E-cadherin." Oncogene 39.1 (2020) : 219-233.
[11] Forte, Luca, et al. "The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer." BMC cancer 18 (2018): 1-11.
[12] Chiu, Kuo-Liang, et al. "ADAM9 enhances CDCP1 by inhibiting miR-1 through EGFR signaling activation in lung cancer metastasis." Oncotarget 8.29 (2017). : 47365.
[13] Emerling, Brooke M., et al. "Identification of CDCP1 as a hypoxia-inducible factor 2α (HIF-2α) target gene that is associated with survival in clear cell renal cell carcinoma patients." Proceedings of the National Academy of Sciences 110.9 (2013): 3483-3488.
[14] Chandrasekaran, Balaji, et al. "Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)." Cancers 15.6 (2023): 1769.
[15] Ji, Donglei, et al. "Targeting CDCP1 gene transcription coactivated by BRD4 and CBP/p300 in castration-resistant prostate cancer." Oncogene 41.23 ( 2022): 3251-3262.
[16] Alajati, A., J. Chen, and A. Alimonti. "CDCP1 initiates tumorigenesis and cooperates with PTEN loss to promote senescence evasion and prostate cancer progression." Annals of Oncology 28 (2017): v1.
[17] Chou, Chiang-Ting, et al. "Prognostic significance of CDCP1 expression in colorectal cancer and effect of its inhibition on invasion and migration." Annals of surgical oncology 22 (2015): 4335-4343.
[18] Karachaliou, Niki, et al. "Common co-activation of AXL and CDCP1 in EGFR-mutation-positive non-small cell lung cancer associated with poor prognosis. " EBioMedicine 29 (2018): 112-127.
[19] Jiang, Tao, et al. "Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta- analysis." Cancer Medicine 5.6 (2016): 1055-1065.
[20] Chiu, Kuo-Liang, et al. "ADAM9 enhances CDCP1 protein expression by suppressing miR-218 for lung tumor metastasis." scientific reports 5.1 (2015). 16426.
[21] Kuhara, Keisuke, et al. "CUB domain-containing protein 1 (CDCP1) is down-regulated by active hexose-correlated compound in human pancreatic cancer cells." Anticancer Research 38.11 (2018): 6107-6111.
[22] Alajati, Abdullah, et al. "Interaction of CDCP1 with HER2 enhances HER2-driven tumorigenesis and promotes trastuzumab resistance in breast cancer." Cell reports 11.4 (2015): 564-576.
[23] Cui, Yan-Hong, et al. "FBXL14 abolishes breast cancer progression by targeting CDCP1 for proteasomal degradation." Oncogene 37.43 (2018): 5794-5809.
[24] Shen, N., et al. "Effect of NLK on the proliferation and invasion of laryngeal carcinoma cells by regulating CDCP1." European Review for Medical & Pharmacological Sciences 23.14 (2019).
[25] Huang, Lijun, et al. "CUB domain-containing protein-1 promotes proliferation, migration and invasion in cervical cancer cells." Cancer Management and Research (2020): 3759-3769.
[26] Cao, Manqing, et al. "HIF-2α regulates CDCP1 to promote PKCδ-mediated migration in hepatocellular carcinoma." Tumor Biology 37 (2016): 1651-1662.
[27] Gioia, Romain, et al. "Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells." Blood, The Journal of the American Society of Hematology 118.8 (2011): 2211-2221.
[28] Heitmann, Jonas S., et al. "Identification of CD318 (CDCP1) as novel prognostic marker in AML." Annals of Hematology 99 (2020): 477-486.
[29] Ebian, Huda F., et al. "Evaluation of CDCP1 (CD318) and endoglin (CD105) expression as prognostic markers in acute myeloid leukemia." Cancer Biomarkers 34.2 (2022): 285-296.
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