Biomedical subjects

Chikako Fukukawa

Publications and source records attributed to Chikako Fukukawa.

4 recordsLinked to original sources

PubMed2005

Therapeutic potential of antibodies against FZD 10, a cell-surface protein, for synovial sarcomas.

Genome-wide expression profiling revealed overexpression of the gene encoding frizzled homologue 10 (FZD 10), a cell-surface receptor for molecules in the Wnt pathway, as a potential contributor to synovial sarcomas (SS). Northern blotting and immunohistochemical staining confirmed that expression levels of FZD 10 were very high in nearly all SS tumors and cell lines examined but absent in most normal organs or in some cancers arising in other tissues. Treatment of human SS cells with small-interfering RNA (siRNA) to FZD 10 decreased the amount of its product and suppressed growth of SS cells. Moreover, a polyclonal antibody specifically recognizing the extracellular domain (ECD) of FZD 10 was markedly effective in mediating ADCC against FZD 10-overexpressing synovial sarcoma cells in vitro. Injection of the antibody into SS xenografts in nude mice attenuated tumor growth, and TUNEL assays revealed clusters of apoptotic cells in antibody-treated xenografts. Taken together, these findings suggest that a humanized antibody against FZD 10 might be a promising treatment for patients with tumors that overexpress FZD 10; minimal or no adverse reactions would be expected because FZD 10 protein is not abundant in vital organs.

Amino Acid Sequence↗

PubMed2005

Molecular target therapy for synovial sarcoma.

Although the specific chromosomal translocation and fusion gene SYT-SSX in synovial sarcoma (SS) has been identified, the molecular mechanism of its tumorigenesis is largely unknown. Recent gene-expression profiles of soft-tissue tumors using cDNA microarray demonstrated that SS has the distinct gene-expression pattern from other sarcomas and has a similar pattern to that of malignant peripheral nerve sheath tumors, indicating that the origin of SS is likely to be the neural crest cells. Through this analysis, several genes were found to be specifically upregulated in SS and considered to play an important role in the proliferation of SS cells. Among them, Frizzled homolog 10 was identified as a good candidate molecule for the development of novel therapies to treat SS patients.

Antineoplastic Agents↗

PubMed2005

The oncoprotein I-2PP2A/SET negatively regulates the MEK/ERK pathway and cell proliferation.

I-2PP2A/SET, the translocation breakpoint-encoded protein expressed in acute undifferentiated leukemia, was identified as an inhibitor of protein phosphatase 2A (PP2A). Induction of exogenous I-2PP2A/SET at a ratio of 1:1 to the endogenous protein resulted in suppression of cell proliferation. In contrast, siRNA-mediated depletion of I-2PP2A/SET resulted in enhanced cell proliferation. Depletion of I-2PP2A/SET was accompanied with a decrease in the number of cells in G1 and an increase in cells in S phase. To examine the mode of action by which I-2PP2A/SET suppresses cell proliferation, we determined the effect of over-expressed I-2PP2A/SET on ERK activation. I-2PP2A/SET suppressed activation of ERK following EGF stimulation but did not affect activation levels of stress kinases, JNK and p38. By contrast, knocking down I-2PP2A/SET by siRNA resulted in enhancement of ERK and MEK activations, suggesting that I-2PP2A/SET negatively regulates MEK/ERK. These data suggest that I-2PP2A/SET negatively regulates cell growth by inhibiting the G1/S transition and inhibiting the MEK/ERK pathway stimulated by external stimuli. These data demonstrate that I-2PP2A/SET potentially functions as a tumor suppressor.

Cell Cycle↗

PubMed2004

pp32/ I-1(PP2A) negatively regulates the Raf-1/MEK/ERK pathway.

In this study, we focus on the potential interaction of pp32/I-1(PP2A) (pp32) with the Raf-MEK-ERK signaling pathway. We show that overexpressed pp32 suppresses Raf-1 activation, thereby downregulating the level of ERK activation. This suppression of Raf-1 requires the C-terminal half of pp32. Conversely, knock-down of PP32 by siRNA enhances ERK and MEK activations. Taken together, we propose that tumor-suppression by pp32 is, at least in part, mediated by downregulation of the Raf-MEK-ERK signaling pathway.

Animals↗