K. Kiguchi - Academia.edu (original) (raw)

Papers by K. Kiguchi

Research paper thumbnail of Induction of cell differentiation in melanoma cells by inhibitors of IMP dehydrogenase: altered patterns of IMP dehydrogenase expression and activity

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1990

To study the induction of differentiation in human melanoma cells, we treated 12 melanoma cell li... more To study the induction of differentiation in human melanoma cells, we treated 12 melanoma cell lines with mycophenolic acid and tiazofurin, inhibitors of IMP dehydrogenase (IMPDH). In all cell lines studied, both agents inhibited cell growth and increased melanin content. However, the degree of growth inhibition did not necessarily correspond to the increase in melanin content. A detailed analysis of the HO and SK-MEL-131 cell lines indicated that mycophenolic acid and tiazofurin caused a time- and dose-dependent increase in the expression of a series of other maturation markers, including formation of dendrite-like structures, tyrosinase activity, and reactivity with the CF21 monoclonal antibody. The growth inhibition and melanogenesis induced by the IMPDH inhibitors was abrogated by the addition of exogenous guanosine. No such effect was observed after treatment of the cells with phorbol 12-myristate 13-acetate or retinoic acid, two other inducers of differentiation in these cells...

Research paper thumbnail of Therapeutic Effect of Rapamycin on Gallbladder Cancer in a Transgenic Mouse Model

Cancer Research, 2007

The macrolide fungicide rapamycin has shown significant antiproliferative action toward a variety... more The macrolide fungicide rapamycin has shown significant antiproliferative action toward a variety of tumor types. In this study, we used BK5.erbB2 transgenic mice as an animal model to examine the therapeutic effect of rapamycin as a potential treatment for gallbladder cancer. Homozygous BK5.erbB2 mice overexpressing the wild-type rat erbB2 gene in basal epithelial cells of the gallbladder have an f70% incidence of gallbladder adenocarcinoma by 2 to 3 months of age. Groups of mice (f2-3 months of age) were treated with rapamycin by i.p. injection (once daily for 14 days) and then sacrificed 24 h after the last treatment. Rapamycin significantly reduced the incidence and severity of gallbladder carcinoma in BK5.erbB2 mice in a dose-dependent manner. Tumors responsive to treatment exhibited a higher number of apoptotic cells. Furthermore, rapamycin treatment led to decreased levels of phosphorylated p70 S6 kinase (Thr 389 ) in gallbladder tissue as assessed by both Western blot and immunofluorescence analyses. Finally, immunofluorescence staining revealed elevated phosphorylated Akt (Ser 473 ) and phosphorylated mammalian target of rapamycin (mTOR; Ser 2448 ) in human gallbladder cancer compared with normal gallbladder tissue. Based on our results using a novel genetically engineered mouse model and the fact that the Akt/mTOR pathway is activated in human gallbladder cancer, rapamycin and related drugs may be effective therapeutic agents for the treatment of human gallbladder cancer. [Cancer Res 2007;67(8):3794-800] Note: Current address for T. Ajiki:

Research paper thumbnail of Glycosphingolipid patterns in human promyelocytic HL-60 leukemia cells susceptible or resistant to differentiation induction by phorbol 12-myristate 13-acetate

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1993

The patterns of glycosphingolipids (GSLs) were analyzed in an HL-60 cell variant, HL-205, which i... more The patterns of glycosphingolipids (GSLs) were analyzed in an HL-60 cell variant, HL-205, which is susceptible to phorbol 12-myristate 13-acetate (PMA)-induced monocyte/macrophage differentiation, and in an HL-60 cell variant, HL-525, which is resistant to such differentiation. The amounts and types of the GSLs were similar in both the HL-205 and HL-525 cells and they resemble those of granulocytes. Treatment with 3 nM PMA caused the susceptible HL-205 cells (but not the resistant cells) to acquire a new GSL pattern which resembles that of monocytes. This new pattern was characterized by increases in the level of a neutral GSL, Gb3Cer, from trace levels to 0.05 mg/109 cells and of an acidic GSL, GM3 ganglioside, from 0.03 to 0.33 mg/109 cells. The increases in the level of this ganglioside were found to be due to an increase in CMP-N-acetylneuraminic acid : lactosylceramide sialyltransferase activity. These results indicate an association between PMA-induced terminal differentiation along the monocyte/macrophage cell lineage and PMA-evoked increases in specific GSLs, GM3 in particular, which is due to a rise in the activity of its synthetic enzyme. 10% solution of benzoylchloride in pyridine following the method of Uilman and McCluer . Analyses

Research paper thumbnail of Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis

Oncogene, 2012

Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of maligna... more Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.

Research paper thumbnail of Induction of cell differentiation in melanoma cells by inhibitors of IMP dehydrogenase: altered patterns of IMP dehydrogenase expression and activity

Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, 1990

To study the induction of differentiation in human melanoma cells, we treated 12 melanoma cell li... more To study the induction of differentiation in human melanoma cells, we treated 12 melanoma cell lines with mycophenolic acid and tiazofurin, inhibitors of IMP dehydrogenase (IMPDH). In all cell lines studied, both agents inhibited cell growth and increased melanin content. However, the degree of growth inhibition did not necessarily correspond to the increase in melanin content. A detailed analysis of the HO and SK-MEL-131 cell lines indicated that mycophenolic acid and tiazofurin caused a time- and dose-dependent increase in the expression of a series of other maturation markers, including formation of dendrite-like structures, tyrosinase activity, and reactivity with the CF21 monoclonal antibody. The growth inhibition and melanogenesis induced by the IMPDH inhibitors was abrogated by the addition of exogenous guanosine. No such effect was observed after treatment of the cells with phorbol 12-myristate 13-acetate or retinoic acid, two other inducers of differentiation in these cells...

Research paper thumbnail of Therapeutic Effect of Rapamycin on Gallbladder Cancer in a Transgenic Mouse Model

Cancer Research, 2007

The macrolide fungicide rapamycin has shown significant antiproliferative action toward a variety... more The macrolide fungicide rapamycin has shown significant antiproliferative action toward a variety of tumor types. In this study, we used BK5.erbB2 transgenic mice as an animal model to examine the therapeutic effect of rapamycin as a potential treatment for gallbladder cancer. Homozygous BK5.erbB2 mice overexpressing the wild-type rat erbB2 gene in basal epithelial cells of the gallbladder have an f70% incidence of gallbladder adenocarcinoma by 2 to 3 months of age. Groups of mice (f2-3 months of age) were treated with rapamycin by i.p. injection (once daily for 14 days) and then sacrificed 24 h after the last treatment. Rapamycin significantly reduced the incidence and severity of gallbladder carcinoma in BK5.erbB2 mice in a dose-dependent manner. Tumors responsive to treatment exhibited a higher number of apoptotic cells. Furthermore, rapamycin treatment led to decreased levels of phosphorylated p70 S6 kinase (Thr 389 ) in gallbladder tissue as assessed by both Western blot and immunofluorescence analyses. Finally, immunofluorescence staining revealed elevated phosphorylated Akt (Ser 473 ) and phosphorylated mammalian target of rapamycin (mTOR; Ser 2448 ) in human gallbladder cancer compared with normal gallbladder tissue. Based on our results using a novel genetically engineered mouse model and the fact that the Akt/mTOR pathway is activated in human gallbladder cancer, rapamycin and related drugs may be effective therapeutic agents for the treatment of human gallbladder cancer. [Cancer Res 2007;67(8):3794-800] Note: Current address for T. Ajiki:

Research paper thumbnail of Glycosphingolipid patterns in human promyelocytic HL-60 leukemia cells susceptible or resistant to differentiation induction by phorbol 12-myristate 13-acetate

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1993

The patterns of glycosphingolipids (GSLs) were analyzed in an HL-60 cell variant, HL-205, which i... more The patterns of glycosphingolipids (GSLs) were analyzed in an HL-60 cell variant, HL-205, which is susceptible to phorbol 12-myristate 13-acetate (PMA)-induced monocyte/macrophage differentiation, and in an HL-60 cell variant, HL-525, which is resistant to such differentiation. The amounts and types of the GSLs were similar in both the HL-205 and HL-525 cells and they resemble those of granulocytes. Treatment with 3 nM PMA caused the susceptible HL-205 cells (but not the resistant cells) to acquire a new GSL pattern which resembles that of monocytes. This new pattern was characterized by increases in the level of a neutral GSL, Gb3Cer, from trace levels to 0.05 mg/109 cells and of an acidic GSL, GM3 ganglioside, from 0.03 to 0.33 mg/109 cells. The increases in the level of this ganglioside were found to be due to an increase in CMP-N-acetylneuraminic acid : lactosylceramide sialyltransferase activity. These results indicate an association between PMA-induced terminal differentiation along the monocyte/macrophage cell lineage and PMA-evoked increases in specific GSLs, GM3 in particular, which is due to a rise in the activity of its synthetic enzyme. 10% solution of benzoylchloride in pyridine following the method of Uilman and McCluer . Analyses

Research paper thumbnail of Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis

Oncogene, 2012

Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of maligna... more Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.