Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms

Abstract

Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell motility. Indeed, PDPN may serve as a chemotherapeutic target for primary and metastatic cancer cells, particularly oral squamous cell carcinoma (OSCC) cells that cause most oral cancers. Here, we studied how a monoclonal antibody (NZ-1) and lectin (MASL) that target PDPN affect human OSCC cell motility and viability. Both reagents inhibited the migration of PDPN expressing OSCC cells at nanomolar concentrations before inhibiting cell viability at micromolar concentrations. In addition, both reagents induced mitochondrial membrane permeability transition to kill OSCC cells that express PDPN by caspase independent nonapoptotic necrosis. Furthermore, MASL displayed a surprisingly robust ability to target PDPN on OSCC cells within minutes of exposure, and significantly inhibited human OSCC dissemination in zebrafish embryos. Moreover, we report that human OSCC cells formed tumors that expressed PDPN in mice, and induced PDPN expression in infiltrating host murine cancer associated fibroblasts. Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.

PKA and CDK5 can phosphorylate specific serines on the intracellular domain of podoplanin (PDPN) to inhibit cell motility

“…Several ligands can bind to the extracellular region of PDPN to promote transformed cell migration and tumorigenesis [37–40]. Accordingly, this extracellular region can be targeted by reagents to inhibit tumor cell growth and motility [15, 25, 27, 28]. …”

“…For example, PDPN promotes the motility and invasion of many transformed cell types including mammary carcinoma [6, 11], glioma [12], and oral squamous carcinoma cells [13–15]. PDPN is also expressed by lymphatic endothelial cells [16, 17] and cancer associated fibroblasts [18–20] which can augment tumor invasion and metastasis [19, 21, 22].…”

“…Indeed, the extracellular domain of PDPN can be targeted by antibodies and specific lectins to suppress tumor cell growth and migration [15, 23–28]. However, signaling events mediated by the intracellular domain of PDPN may also illuminate mechanisms leading to cell motility and pathways to chemotherapy that have not been explored.…”

Components in aqueous Hibiscus rosa-sinensis flower extract inhibit in vitro melanoma cell growth

“…B16, NIH3T3, and LA25 cells were maintained in DMEM (Hyclone SH30021) supplemented with 25 mM HEPES (Hyclone SH3027) and 10% FBS (Seradigm 1400-500) at 37 °C in 5% CO2 and 100% humidity as described 14, 15, 16, 17, 18. B16 and NIH3T3 cells were plated at 5000 cells/well in standard 24 well culture plates and allowed to adhere to plates for 24 h. Different concentrations of aqueous plant extract were then added and cells were incubated for an additional 72 h. LA25 cells were grown overnight at non permissive temperature (40 °C) before being incubated for 24 h at permissive (33 °C) and nonpermissive (40 °C) temperatures with or without hibiscus extract, and then stained with Trypan blue to distinguish living and dead cells.…”

Podoplanin Expression in Canine Melanoma

“…(4) PDPN activates platelet aggregation by binding to Ctype lectin-like receptor-2 (CLEC-2) on platelets, (6,7) and the PDPN-CLEC-2 interaction facilitates blood/lymphatic vessel separation. (8) The expression of human PDPN was reported in many tumors, including oral cancers, (9) malignant brain tumors, (10)(11)(12) lung cancers, (13) esophageal cancers, (14) malignant mesotheliomas, (15) testicular tumors, (16) and osteosarcomas. (17) PDPN expression is also associated with cancer metastasis and malignant progression.…”