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Tomoharu Fukumori

Publications and source records attributed to Tomoharu Fukumori.

At least 19 recordsLinked to original sources
PubMed2006

Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer.

Prostate cancer is one of the malignant tumors which exhibit resistance to anticancer drugs, at least in part due to enhanced antiapoptotic mechanisms. Therefore, the understanding of such mechanisms should improve the design of chemotherapy against prostate cancer. Galectin-3 (Gal-3), a multifunctional oncogenic protein involved in the regulation of tumor proliferation, angiogenesis, and apoptosis has shown antiapoptotic effects in certain cell types. Here, we show that the expression of exogenous Gal-3 in human prostate cancer LNCaP cells, which do not express Gal-3 constitutively, inhibits anticancer drug-induced apoptosis by stabilizing the mitochondria. Thus, Gal-3-negative cells showed 66.31% apoptosis after treatment with 50 micromol/L cis-diammine-dichloroplatinum for 48 hours, whereas two clones of Gal-3-expressing cells show only 2.92% and 1.42% apoptotic cells. Similarly, Gal-3-negative cells showed 43.8% apoptosis after treatment with 300 micromol/L etoposide for 48 hours, whereas only 15.38% and 14.51% of Gal-3-expressing LNCaP cells were apoptotic. The expression of Gal-3 stimulated the phosphorylation of Ser(112) of Bcl-2-associated death (Bad) protein and down-regulated Bad expression after treatment with cis-diammine-dichloroplatinum. Gal-3 also inhibited mitochondrial depolarization and damage after translocation from the nuclei to the cytoplasm, resulting in inhibition of cytochrome c release and caspase-3 activation. These findings indicate that Gal-3 inhibits anticancer drug-induced apoptosis through regulation of Bad protein and suppression of the mitochondrial apoptosis pathway. Therefore, targeting Gal-3 could improve the efficacy of anticancer drug chemotherapy in prostate cancer.

Apoptosis↗
PubMed2006

Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand.

TRAIL/Apo2L is a pro-apoptotic cytokine that is capable of inducing apoptosis in a wide variety of cancer cells but not in normal cells. Among various molecular strategies by which cancer cells evade apoptosis, PI3K/Akt signaling represents a dominant survival pathway. In this report, we investigated the role of PI3K/Akt pathway in TRAIL-induced apoptotic death in human bladder cancer cells. We observed that RT4 cells had very low level of constitutively active Akt and were sensitive to TRAIL, whereas UM-UC-3 and T24 cells had higher levels of constitutively active Akt and were resistant to TRAIL. Downregulation of constitutively active Akt by PI3K inhibitors, wortmannin and LY294002, reversed cellular resistance to TRAIL. However, transfecting constitutively active Akt into RT4 cells increased Akt activity and inhibited TRAIL-induced apoptosis. These results suggest that elevated Akt activity protects UM-UC-3 and T24 cells from TRAIL-induced apoptosis, and the PI3K/Akt signaling might inhibit apoptotic signals. Thus, the modulation of Akt activity by combining pharmacological drugs or genetic alterations of the Akt expression could induce cellular responsiveness to TRAIL and PI3K/Akt signaling pathway could serve as a novel target for therapeutic intervention in bladder cancer.

Apoptosis↗
PubMed2006

Indications for laparoscopic adrenalectomy for non-functional adrenal tumor with hypertension: usefulness of adrenocortical scintigraphy.

AIM: Laparoscopic adrenalectomy is currently indicated for biochemically and clinically functional adrenal tumors and potentially malignant tumors of the adrenal glands. Non-functional adenomas greater than 5 cm in diameter of the adrenal gland are generally considered to represent potentially malignant tumors. The present study shows indications of laparoscopic adrenalectomy for non-functional adrenal tumors with hypertension in a retrospective fashion. METHODS: Between 1994 and 2004, 110 laparoscopic adrenalectomies were performed at Tokushima University Hospital. All 110 patients underwent detailed endocrinological examination before surgery. Medical and operative records of these 110 patients (57 men, 53 women), including operative parameters, histopathological findings and pre- and postoperative hypertension, were reviewed. Forty-five patients underwent laparoscopic adrenalectomy for non-functional adrenal tumors, and [(131)I]6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol (NP-59) scintigraphy was performed for patients with preoperative hypertension. RESULTS: Mean patient age was 55.0 years (range, 22-77 years). Mean maximum tumor diameter was 42 mm (range, 20-105 mm). All adrenal tumors were removed successfully by laparoscopic surgery. Hypertension was postoperatively improved in seven of the 11 patients with preoperative hypertension, without subclinical Cushing syndrome. Importantly, all patients who improved hypertension after adrenalectomy displayed strong accumulation in adrenal tumors with visualization of the contralateral gland on NP-59 scintigraphy. Conversely, blood pressure did not improve in four patients for whom scintigraphy yielded negative results. CONCLUSIONS: The indication of laparoscopic adrenalectomy for non-functional adrenal tumors is generally considered for lesions more than 5 cm diameter. However, the present study suggests that laparoscopic surgery should be considered even in patients with tumors less than 5 cm in diameter, if both hypertension and accumulation in tumors on NP-59 scintigraphy are present.

Adenoma↗
PubMed2006

Bilateral adrenal myelolipoma associated with adrenogenital syndrome.

Adrenal myelolipoma is a rare benign tumor, occasionally reported in association with endocrine disorders. We report herein a case of bilateral adrenal myelolipoma associated with adrenogenital syndrome caused by 21-hydroxylase deficiency. A diagnosis of 21-hydroxylase deficiency was confirmed by mutation analysis of the CYP21 gene. Our case represents only the second case of bilateral adrenal myelolipoma associated with adrenogenital syndrome caused by 21-hydroxylase deficiency.

Adrenal Hyperplasia, Congenital↗
PubMed2006

Clinical research of renal vein control using Hem-o-lok clips in laparoscopic nephrectomy.

Control of the renal vein represents a crucial step in laparoscopic nephrectomy. Although endovascular gastrointestinal anastomosis (GIA) staplers have generally been used for renal vein control because of the large diameter of the vessel, Hem-o-lok clips have recently been used for renal artery control. GIA staplers are expensive and can malfunction on rare occasions, resulting in severe complications. We evaluated renal vein control using Hem-o-lok clips (adaptive vascular width 7-16 mm) in laparoscopic nephrectomy. Since April 2004, we have ligated renal arteries using Hem-o-lok clips. From June 2004, this method was applied for renal vein control in 40 laparoscopic nephrectomies. After renal pedicle dissection, renal pedicle ligation was accomplished using extra large (XL) Hem-o-lok clips on both the renal arteries and veins by placing two clips on the patient side and one clip on the specimen side. Ligation times for obtaining renal vein control were compared between XL Hem-o-lok clips and GIA staplers in 40 cases before June 2004. Vascular control using XL Hem-o-lok clips was successful in all 40 cases, without any slipping of clips or uncontrolled bleeding. After renal pedicle dissection, ligation time for achieving renal vein control was 167.0 +/- 48 s (range: 122-295 s) using XL Hem-o-lok clips (mean, three clips) and 68 +/- 24.0 s (range: 54-150 s) using a GIA stapler. XL Hem-o-lok clips allow safe and reliable control of renal veins in laparoscopic nephrectomy. Ligation time is only 100 s longer than using a GIA stapler. In addition, costs are reduced by more than 90% compared to GIA stapling.

Adult↗
PubMed2006

Prostate stem cell antigen predicts tumour recurrence in superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: To evaluate the relationship between prostate stem cell antigen (PSCA) expression level in transitional cell carcinoma (TCC) of the urinary bladder and various clinicopathological features, including stage and grade; and to determine whether PSCA mRNA expression predicts disease recurrence in superficial (not muscle-invasive) TCC of the bladder. PATIENTS AND METHODS: Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on 97 TCC tissue samples and in 36 samples of normal bladder urothelium; the findings were analysed in relation to clinicopathological factors. Immunohistochemical expression was examined using light and confocal immunofluorescence microscopy to validate the RT-PCR data. RESULTS: Twenty-seven patients developed disease recurrence, while the remaining 22 had no evidence of recurrence of superficial TCC of the bladder. There was significantly higher PSCA mRNA expression in TCC than in normal urothelium samples (P = 0.008). Superficial (TaT1) tumours had significantly higher PSCA expression than muscle-invasive (> or = pT2) tumours (P < 0.001). There was no significant difference between patients with G1-2 tumours and those with G3 tumours (P = 0.109). Immunohistochemical analysis showed markedly greater PSCA expression in superficial than invasive TCC. Notably, from a multivariate analysis, the expression level of PSCA was an independent predictor of disease recurrence in superficial TCC (P = 0.012). CONCLUSIONS: These findings suggest that the PSCA expression level measured by real-time RT-PCR could be a valuable prognostic marker for tumour recurrence in superficial TCC of the bladder.

Aged↗
PubMed2006

The expression of prostate stem cell antigen in human clear cell renal cell carcinoma: a quantitative reverse transcriptase-polymerase chain reaction analysis.

OBJECTIVES: To analyse the gene expression level of prostate stem cell antigen (PSCA) in human clear cell renal cell carcinoma (CC-RCC) and its relationship with conventional clinicopathological manifestations, to evaluate its prognostic value for patient outcome, and to determine the effect of PSCA on the progression of CC-RCC. PATIENTS AND METHODS: We quantified PSCA mRNA level in human RCC cell lines (ACHN, A704, KPK-1, Caki-1, and Caki-2) and in 154 surgical tissue samples (81 from CC-RCC, 73 from normal kidney) using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The findings were analysed in relation to clinicopathological factors. Immunohistochemical expression was examined using confocal laser scanning light-microscopy. RESULTS: PSCA was overexpressed in all RCC cell lines. PSCA mRNA levels were significantly higher in CC-RCC than in normal kidney tissue samples (P < 0.001), in G2-G3 than in G1 tumours (P = 0.028), and in advanced disease (T3-T4) than in organ-confined (T1-T2) tumours (P = 0.016). There was significantly higher PSCA mRNA expression in patients with M1 than in those with M0 disease (P = 0.029). Patients in whom the lesions had high PSCA expression levels had a significantly worse prognosis than those with low PSCA expression levels (P = 0.044). Using immunohistochemical analysis there was markedly greater PSCA expression in CC-RCC than in normal kidney, and in advanced-disease high-grade tumours than in organ-confined low-grade tumours. CONCLUSIONS: A significant correlation was detected in the gene expression level of PSCA with histological grade, clinicopathological stage and prognosis in CC-RCC. Our data indicate that PSCA is associated with carcinogenesis and progression of CC-RCC.

Antigens, Neoplasm↗
PubMed2006

[A case of renal capsular hemangiosarcoma].

We report herein a case of renal capsular hemangiosarcoma. A 68-year-old man was admitted to our hospital for treatment of a retroperitoneal tumor identified incidentally on abdominal computed tomography (CT) for follow-up of superficial bladder tumor. The tumor was about 7cm in diameter, positioned between the right kidney and the liver. Right nephrectomy was performed under a diagnosis of renal capsular tumor. Pathological diagnosis was hemangiosarcoma and positive surgical margins were suspected. Radiotherapy was performed postoperatively to a total dose of 50 Gy. Hemangiosarcoma frequently occurs in the skin, but is rare in the retroperitoneal cavity. Neither metastasis nor recurrence has been seen as of 19 months postoperatively.

Aged↗
PubMed2006

[Chemotherapy-resistant germ cell cancer of the testis treated by salvage surgery: a case report].

A 38-year-old patient who had a non-seminomatous testicular cancer was treated by resection of the retroperitoneal metastatic mass that had proven refractory to bleomycin, etoposide and cisplatin (BEP) and paclitaxel, ifosfamide and cisplatin (TIP) chemotherapies. Although salvage chemotherapy was given against the chemorefractory metastatic lesions in the retroperitoneum, the serum alpha-fetoprotein level elevated to 3,252 ng/ml. Retroperitoneal lymph node dissection was performed, and viable cells were identified histopathologically in the resected tissues. The serum AFP level normalized after surgery. No recurrence has been observed for 22 months postoperatively. This experience indicates that salvage surgery even under high serum marker levels may have a beneficial outcome for selected cases of chemotherapy-resistant germ cell tumors.

Adult↗
PubMed2006

[A non-seminomatous extra-gonadal germ cell tumor responding to intensive treatment: a case report].

A 23-year-old man presented with lumbago as a chief complaint. Computed tomographic (CT) scan revealed multiple lung tumors, multiple liver tumors, bulky retroperitoneal tumors with marked elevation of serum lactic dehydrogenase (LDH), alpha-fetoprotein, and beta subunit of human chorionic gonadotropin (HCG-beta). The patient was referred to our hospital for treatment. Scrotal ultrasonography and physical examination revealed bilateral normal testes. Because of bulky retroperitoneal masses with elevated specific tumor markers as well as bilateral normal testes, our diagnosis led to extra-gonadal germ cell tumor. Because the pulmonary lesion had increased rapidly, chemotherapy was performed without the tumor biopsy. After multiple chemotherapy regimens including BEP (bleomycin, etoposide, cisplatin), high-dose chemotherapy, and TIN (paclitaxel, ifosfamide, nedaplatin), all tumor marker levels fell into within the normal range. The tumor size was decreased remarkably on CT. Then, retroperitoneal lymphadenectomy were performed to confirm whether they still contained viable tumor cells. They contained only necrotic tissues without viable cancer cells by pathological examination. Consequently, the patient has been free of recurrence for 18 months after intensive treatment.

Adult↗
PubMed2005

Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells.

The antiapoptotic molecule galectin-3 was previously shown to regulate CD95, a member of the tumor necrosis factor (TNF) family of proteins in the apoptotic signaling pathway. Here, we question the generality of the phenomenon by studying a different member of this family of proteins [e.g., TNF-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a wide variety of cancer cells]. Overexpression of galectin-3 in J82 human bladder carcinoma cells rendered them resistant to TRAIL-induced apoptosis, whereas phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin and LY-294002) blocked the galectin-3 protecting effect. Because Akt is a major downstream PI3K target reported to play a role in TRAIL-induced apoptosis, we questioned the possible relationship between galectin-3 and Akt. Parental J82 and the control vector-transfected J82 cells (barely detectable galectin-3) exhibit low level of constitutively active Akt, resulting in sensitivity to TRAIL. On the other hand, J82 cells overexpressing galectin-3 cells expressed a high level of constitutively active Akt and were resistant to TRAIL. Moreover, the blockage of TRAIL-induced apoptosis in J82 cells seemed to be mediated by Akt through the inhibition of BID cleavage. These results suggest that galectin-3 involves Akt as a modulator molecule in protecting bladder carcinoma cells from TRAIL-induced apoptosis.

Apoptosis↗
PubMed2005

Implication of galectin-3 in Wnt signaling.

Galectin-3 (gal-3), a member of the beta-galactoside-binding proteins family, was identified as a binding partner of beta-catenin. Analysis of the human gal-3 sequence reveled a structural similarity to beta-catenin as it also contains the consensus sequence (S92XXXS96) for glycogen synthase kinase-3beta (GSK-3beta) phosphorylation and can serve as its substrate. In addition, Axin, a regulator protein of Wnt that complexes with beta-catenin, also binds gal-3 using the same sequence motif identified here by a deletion mutant analysis. The data presented here give credence to the suggestion that gal-3 is a key regulator in the Wnt/beta-catenin signaling pathway and highlight the functional similarities between gal-3 and beta-catenin.

Animals↗
PubMed2004

Endogenous galectin-3 determines the routing of CD95 apoptotic signaling pathways.

Studies of CD95 (APO-1/Fas), a member of the death receptor family, have revealed that it is involved in two primary CD95 apoptotic signaling pathways, one regulated by the large amount of active caspase-8 (type I) formed at the death-inducing signaling complex and the other by the apoptogenic activity of mitochondria (type II). To date, it is still unclear which pathway will be activated in response to an apoptotic insult. Here, we demonstrate that the antiapoptotic molecule galectin-3, which contains the four amino acid-anti-death-motif (NWGR) conserved in the BH1 domain of the Bcl-2 member proteins, is expressed only in type I cells. Transfection of galectin-3 cDNA into galectin-3 null cells (type II) resulted converting them to type I apoptotic phenotype. In addition, we show that galectin-3 is complexed with CD95 in vivo identifying galectin-3 as a novel CD95-binding partner that determines which of the CD95 apoptotic signaling pathways the cell will select.

Apoptosis↗
PubMed2004

Nuclear export of phosphorylated galectin-3 regulates its antiapoptotic activity in response to chemotherapeutic drugs.

Galectin-3 (Gal-3), a member of the beta-galactoside binding protein family containing the NWGR antideath motif of the Bcl-2 protein family, is involved in various aspects of cancer progression. Previously, it has been shown that the antiapoptotic activity of Gal-3 is regulated by the phosphorylation at Ser(6) by casein kinase 1 (CK1). Here we questioned how phosphorylation at Ser(6) regulates Gal-3 function. We have generated serine-to-alanine (S6A) and serine-to-glutamic acid (S6E) Gal-3 mutants and transfected them into the BT-549 human breast carcinoma cell line, which does not express Gal-3. BT-549 cell clones expressing wild-type (wt) and mutant Gal-3 were exposed to chemotherapeutic anticancer drugs. In response to the apoptotic insults, phosphorylated wt Gal-3 was exported from the nucleus to the cytoplasm and protected the BT-549 cells from drug-induced apoptosis while nonphosphorylated mutant Gal-3 neither was exported from the nucleus nor protected BT-549 cells from drug-induced apoptosis. Furthermore, leptomycin B, a nuclear export inhibitor, increased the cisplatin-induced apoptosis of Gal-3 expressing BT-549 cells. These results suggest that Ser(6) phosphoryaltion acts as a molecular switch for its cellular translocation from the nucleus to the cytoplasm and, as a result, regulates the antiapoptotic activity of Gal-3.

Active Transport, Cell Nucleus↗
PubMed2003

CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis.

Galectin (Gal)-3, a M(r) 31000 member of the beta-galactoside-binding protein family, is a multifunctional protein implicated in a variety of biological functions, including tumor cell adhesion, proliferation, differentiation, angiogenesis, apoptosis, cancer progression, and metastasis. Here, we report that secreted extracellular Gal-3 can signal apoptosis of human T leukemia cell lines, human peripheral blood mononuclear cells, and activated mouse T cells after binding to cell surface glycoconjugate receptors through carbohydrate-dependent interactions because the apoptotic effect was found to be inhibited by lactose, specific sugar inhibitor, and to be dose dependent. However, the apoptosis sensitivity to Gal-3 varied among the different cell lines tested. We report that Gal-3-null Jurkat, CEM, and MOLT-4 cells were significantly more sensitive to exogenous Gal-3 than SKW6.4 and H9 cells, which express Gal-3, suggesting a cross-talk between the antiapoptotic activity of intracellular Gal-3 and proapoptotic activity of extracellular Gal-3. Furthermore, Gal-3-transfected CEM cells were found to be more resistant to C(2)-ceramide-induced apoptosis than the control CEM cells. Identification of Gal-3 cell surface receptors revealed that Gal-3 binding to CD7 and CD29 (beta(1) integrin) induced apoptosis. Gal-3 binding to its cell surface receptors results in activation of mitochondrial apoptosis events including cytochrome c release and caspase-3 activation, but not caspase-8 activation. Taken together, these results suggest that the induction of T-cell apoptosis by secreted Gal-3 may play a role in the immune escape mechanism during tumor progression through the induction of apoptosis to cancer-infiltrating T cells. The induction of T-cell apoptosis by secreted Gal-3 is dependent in part on the presence or absence of cytoplasmic Gal-3, providing a new insight for the immune escape mechanism of cancer cells.

Animals↗
PubMed2003

Regulation of cell proliferation by autocrine motility factor/phosphoglucose isomerase signaling.

Autocrine motility factor (AMF)/phosphoglucose isomerase (PGI; EC 5.3.1.9) is a housekeeping cytosolic enzyme that plays a key role in both glycolysis and gluconeogenesis pathways. AMF/PGI is also a multifunctional protein that displays cytokine properties, eliciting mitogenic, motogenic, and differentiation activities, and has been implicated in tumor progression and metastasis. Because little is known about AMF/PGI-dependent signaling in general and during tumorigenesis in particular, we sought to study its effect on the cell cycle. To elucidate the functional role of PGI, we stably transfected its cDNA into NIH/3T3 and BALB/c 3T3-A31 fibroblasts. Ectopic overexpression of PGI results in the acquisition of a transformed phenotype associated with an acceleration of G1 to S cell cycle transition. These were manifested by up-regulation of cyclin D1 expression and cyclin-dependent kinase activity and down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. The reduced p27Kip1 protein expression level in PGI-overexpressing cells could be restored to control levels by treatment with proteasome inhibitor. PGI-overexpressing cells also exhibited elevated expression of Skp2 involved in p27Kip1 ubiquitination and elevation in the levels of retinoblastoma protein hyperphosphorylation. Thus, we may conclude that the overexpression of AMF/PGI enhances cell proliferation together with up-regulation of cyclin/cyclin-dependent kinase activities and down-regulation of p27Kip1, whereas the induction of 3T3 fibroblast transformation by PGI is regulated by the retinoblastoma protein pathway.

3T3 Cells↗
PubMed2002

Expression of angiostatin cDNA in a murine renal cell carcinoma suppresses tumor growth in vivo.

OBJECTIVES: To investigate the effectiveness of angiostatin gene therapy for renal cancer using a mouse model. The generally poor prognosis of advanced renal cancer indicates the need for new therapeutic modalities. The dependency of solid tumor growth on angiogenesis suggests that antiangiogenic therapy would be effective against renal cell carcinoma, which is generally a hypervascular tumor. METHODS: Murine renal cancer cells (Renca) transfected with murine angiostatin cDNA (AST-Renca) were subcutaneously implanted in BALB/c mice. Subsequently, the macroscopic appearance and volume of tumors were evaluated once per week. Renca cells transfected with empty plasmid DNA (mock-Renca) were used as a control. In addition, histologic sections of tumor were analyzed for neovascularization on the basis of an immunohistochemical analysis for CD31. The antitumor effect of AST-Renca on a parental Renca tumor at a distant site was also evaluated. RESULTS: The mean volume of AST-Renca tumors was significantly less than that of the control vector-transfected tumors 3 weeks after implantation. In the cell proliferation assay, the expression of angiostatin did not inhibit the proliferation of Renca cells in vitro. Immunohistochemical analysis of neovascularization by staining with anti-CD31 antibody revealed that angiostatin suppressed tumor vessel formation. Moreover, implantation of AST-Renca inhibited the growth of parental Renca implanted simultaneously at a distant site. CONCLUSIONS: Expression of an angiostatin transgene can suppress the growth of murine renal cancer through the inhibition of tumor-induced angiogenesis. Angiostatin gene therapy may be effective against renal cancer.

Angiostatins↗