NECTIN-4 In Cancer Research Articles

Therapeutic prospects of nectin-4 in cancer: applications and value.

Nectin-4 is a Ca2+-independent immunoglobulin-like protein that exhibits significantly elevated expression in malignant tumors while maintaining extremely low levels in healthy adult tissues. In recent years, overexpression of Nectin-4 has been implicated in tumor occurrence and development of various cancers, including breast cancer, urothelial cancer, and lung cancer. In 2019, the Food and Drug Administration approved enfortumab vedotin, the first antibody-drug conjugate targeting Nectin-4, for the treatment of urothelial carcinoma. This has emphasized the value of Nectin-4 in tumor targeted therapy and promoted the implementation of more clinical trials of enfortumab vedotin. In addition, many new drugs targeting Nectin-4 for the treatment of malignant tumors have entered clinical trials, with the aim of exploring potential new indications. However, the exact mechanisms by which Nectin-4 affects tumorigenesis and progression are still unclear, and the emergence of drug resistance and treatment-related adverse reactions poses challenges. This article reviews the diagnostic potential, prognostic significance, and molecular role of Nectin-4 in tumors, with a focus on clinical trials in the field of Nectin-4-related tumor treatment and the development of new drugs targeting Nectin-4.

PARP inhibitor Veliparib (ABT-888) enhances the anti-angiogenic potentiality of Curcumin through deregulation of NECTIN-4 in oral cancer: Role of nitric oxide (NO)

Concurrent use of DNA damaging agents with PARP inhibitors contribute to the effectiveness of the anticancer therapy. But there is a dearth of reports on the antiangiogenic effects of PARP inhibitors and the suppression of angiogenesis by this drug combination is not yet reported. For the successful development of cancer therapeutics, anti-cancer drugs ought to have anti-angiogenic potentiality along with their DNA damaging abilities. In this current piece of work, we investigated the in vitro and in ovo anti-angiogenic effect of Curcumin and Veliparib (a PARP inhibitor) in oral cancer. Recent evidences suggest an involvement of the NECTIN-4 in cancer angiogenesis and the exact molecular pathway of this involvement remains to be delineated. We observed that the soluble NECTIN-4 secreted from H357 oral cancer cells enhanced the angiogenesis of endothelial cells (HUVECs) and this was inhibited by Curcumin-Veliparib combination. NECTIN-4 enhanced vascularization, induced vasodilation and triggered the angiogenic sprouting via endothelial tip cell filopodia. Data indicated that NECTIN-4 mediated angiogenesis is associated with PI3K-AKT-mediated nitric oxide (NO) formation. A noticeable increase in the NO enhanced epithelial NO level through HIF-1α mediated iNOS activation. We observed that increased NO enhanced the NECTIN-4 mediated eNOS expression and thereby elicited further angiogenesis. Curcumin antagonised the NECTIN-4-induced angiogenesis through inhibition of PI3K-AKT mediated eNOS pathway and Veliparib synergized the effect of Curcumin. Our observations indicate that NO is cardinal in inducing NECTIN-4 mediated angiogenesis in H357 cells. Thus, Curcumin-Veliparib combination suppresses angiogenesis through deregulation of the PI3K-AKT-eNOS pathway downstream to the NECTIN-4.

Nanoformulated quinacrine regulates NECTIN-4 domain specific functions in cervical cancer stem cells

NECTIN-4 [a poliovirus receptor-related-4 (PVRL-4) encoded gene] has vital roles in cancer proliferation, metastasis and angiogenesis. It possesses three different domains and it is predicted that they have different roles in cancer but the structure-function relationship is still unknown and hence carrying out a detailed study to elucidate the domain-specific functions of NECTIN-4 in cancer is necessary. Using 5-Fluouracil-resistant cervical cancer stem cells (PEMT-5FU-R-MC) and different NECTIN-4 domain-specific constructs, different domains of NECTIN-4 were over-expressed in PEMT-5FU-R-MC cells. Biochemical assays like comet, γ-H2AX immunofluorescence, western blot, in vitro tube formation, gelatin zymography, in ovo CAM assay, etc. were used to delineate the function of each domain of NECTIN-4 in cancer and their regulation by nano-formulated quinacrine (NQC). Endo-domain (lacking extracellular region corresponding to aa 30–347) and ecto-domain (lacking signal peptide and cytoplasmic region corresponding to aa 1–29 and 348–509, respectively) of NECTIN-4 were largely overexpressed in nucleus and cytoplasm, respectively. Endo-domain translocates into nucleus by physically interacting with IMPORTIN-α2, activates the DNA repair and enhances cell growth, whereas ecto-domain specifically activates angiogenesis by modulating representative angiogenic markers, inducing in vitro tube formation and in ovo blood vessel formation. Full-length NECTIN-4 (aa 1-509) was overexpressed in both nucleus and cytoplasm and modulated both DNA repair and angiogenesis. NQC down-regulated these phenomena by modulating the endo-domain and ecto-domain of NECTIN-4. Thus, current study suggested that endo-domain of NECTIN-4 translocated into nucleus and increased the DNA repair and ecto-domain of NECTIN-4 enhanced the angiogenesis, whereas NQC inhibits these processes.