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

Ochoa-Alvarez JA, Krishnan H, Pastorino JG, Nevel E, Kephart D, Lee JJ, Retzbach EP, Shen Y, Fatahzadeh M, Baredes S, Kalyoussef E, Honma M, Adelson ME, Kaneko MK, Kato Y, Young MA, Deluca-Rapone L, Shienbaum AJ, Yin K, Jensen LD, Goldberg GS - Oncotarget (2015)

Bottom Line: 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.Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.

View Article: PubMed Central - PubMed

Affiliation: Departments of Molecular Biology, Cell Biology, and Pathology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Mitochondrial membrane permeability transition inhibition protects cells from NZ-1 and MASL toxicity, while caspase inhibition does notThe effects of the pan-caspase blocker Z-VAD-FMK and the mitochondrial membrane permeability transition blocker cyclosporin A were examined on HSC-2 and HSC-4 cells treated with 2310 nM NZ-1 or MASL as indicated. Data are shown as percent of cells killed (mean+SEM, n=6).
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Figure 7: Mitochondrial membrane permeability transition inhibition protects cells from NZ-1 and MASL toxicity, while caspase inhibition does notThe effects of the pan-caspase blocker Z-VAD-FMK and the mitochondrial membrane permeability transition blocker cyclosporin A were examined on HSC-2 and HSC-4 cells treated with 2310 nM NZ-1 or MASL as indicated. Data are shown as percent of cells killed (mean+SEM, n=6).

Mentions: The pan-caspase blocker Z-VAD-FMK and the mitochondrial membrane permeability transition blocker cyclosporin A were used to further investigate mechanisms underlying MASL and NZ-1 toxicity in HSC-2 and HSC-4 cells. As shown in Figure 7, Z-VAD-FMK did not protect either cell line from MASL or NZ-1 toxicity. In contrast, cyclosporin A decreased toxicity of NZ-1 and MASL by several fold in both cell lines (p<0.0004 by t-test). Taken together, these data indicate that NZ-1 and MASL induce mitochondrial membrane permeability transition to kill OSCC cells by caspase independent nonapoptotic necrosis.


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

Ochoa-Alvarez JA, Krishnan H, Pastorino JG, Nevel E, Kephart D, Lee JJ, Retzbach EP, Shen Y, Fatahzadeh M, Baredes S, Kalyoussef E, Honma M, Adelson ME, Kaneko MK, Kato Y, Young MA, Deluca-Rapone L, Shienbaum AJ, Yin K, Jensen LD, Goldberg GS - Oncotarget (2015)

Mitochondrial membrane permeability transition inhibition protects cells from NZ-1 and MASL toxicity, while caspase inhibition does notThe effects of the pan-caspase blocker Z-VAD-FMK and the mitochondrial membrane permeability transition blocker cyclosporin A were examined on HSC-2 and HSC-4 cells treated with 2310 nM NZ-1 or MASL as indicated. Data are shown as percent of cells killed (mean+SEM, n=6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496201&req=5

Figure 7: Mitochondrial membrane permeability transition inhibition protects cells from NZ-1 and MASL toxicity, while caspase inhibition does notThe effects of the pan-caspase blocker Z-VAD-FMK and the mitochondrial membrane permeability transition blocker cyclosporin A were examined on HSC-2 and HSC-4 cells treated with 2310 nM NZ-1 or MASL as indicated. Data are shown as percent of cells killed (mean+SEM, n=6).
Mentions: The pan-caspase blocker Z-VAD-FMK and the mitochondrial membrane permeability transition blocker cyclosporin A were used to further investigate mechanisms underlying MASL and NZ-1 toxicity in HSC-2 and HSC-4 cells. As shown in Figure 7, Z-VAD-FMK did not protect either cell line from MASL or NZ-1 toxicity. In contrast, cyclosporin A decreased toxicity of NZ-1 and MASL by several fold in both cell lines (p<0.0004 by t-test). Taken together, these data indicate that NZ-1 and MASL induce mitochondrial membrane permeability transition to kill OSCC cells by caspase independent nonapoptotic necrosis.

Bottom Line: 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.Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.

View Article: PubMed Central - PubMed

Affiliation: Departments of Molecular Biology, Cell Biology, and Pathology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.

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.

No MeSH data available.


Related in: MedlinePlus