Futoshi Teranishi

Evidence that de novo protein synthesis is dispensable for anti-apoptotic effects of NF-κB

The transcription factor NF-κB is a positive transcription factor for a number of genes and has been recognized as an anti-apoptotic regulator. However, the mechanism by which NF-κB blocks apoptosis is still controversial. Here, we demonstrate the evidence that NF-κB could attenuate the TNF-α-induced apoptosis without de novo protein synthesis using human pancreatic cancer cell lines, MIA PaCa-2 and Capan-2. The TNF-α-induced apoptosis was blocked by IL-1β, a potent inducer of NF-κB activation. This inhibitory effect of IL-1β was evident when cells were treated with protein synthesis inhibitors such as cycloheximide (CHX). Moreover, NF-κB decoy oligonucleotides could not block the anti-apoptotic effect of IL-1β at doses sufficient to block the NF-κB-dependent transcription induced by IL-1β. To confirm the role of NF-κB in blocking apoptosis, we generated stable cell lines expressing IκBΔN, a highly stable form of IκBα, a cytoplasmic inhibitor of NF-κB. In these stable transfectants, the anti-apoptotic effect of IL-1β was totally abolished, indicating that the anti-apoptotic action of IL-1β could be ascribed to the NF-κB action. These findings show that de novo protein synthesis is dispensable for anti-apoptotic effects of NF-κB and support the possibility that NF-κB could exert its anti-apoptotic action through protein-protein interaction.

Phosphoinositide 3‐kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo

In order to block peritoneal metastasis of pancreatic cancer cells, we have attempted to block the signal transduction pathway involving hyaluronan (HA), Src, phosphoinositide 3‐kinase (PI3K) and Akt. We examined the effects of Src, PI3K and Akt inhibitors on pancreatic cancer cell motility, invasion and metastasis. The pancreatic cancer cell line SW1990, known to cause peritoneal metastasis efficiently in nude mice, was used in this study. SW1990 cells were stimulated by HA to induce Akt phosphorylation. Then, the inhibitory effects of PI3K and Src kinase inhibitors were examined. Cell motility and cell migration assays were adopted to assess the cancer cell motility and its migration capability. We also examined the therapeutic efficacies of PI3K inhibitor wortmannin on peritoneal metastasis of SW1990 cells in the nude mouse model. Stimulation of SW1990 cells by HA markedly induced the Src‐PI3K‐Akt signaling, thus enhancing cancer cell motility and its migration. Significantly, we found that wortmannin could exert marked inhibition of the peritoneal metastasis of SW1990 in nude mice in vivo. These findings indicate that the PI3K‐Akt signaling pathway plays an essential role in peritoneal metastasis and PI3K inhibitors such as wortmannin can be novel modalities to prevent peritoneal metastasis of invasive cancers such as pancreatic cancer. (Cancer Sci 2009; 100: 770–777)

Calpain is involved in the HIV replication from the latently infected OM10.1 cells.

Treatment of OM10.1 cells latently infected with human immunodeficiency virus type 1 (HIV-1) with phorbol ester and calcium ionophore (A23187) induced virus replication which was blocked by N-Ac-Leu-Leu-norleucinal (ALLnL), a calpain inhibitor I, and not by lactacystin, a specific proteasome inhibitor. When the purified NF-kappa B/I kappa B complex was treated with mu-calpain, the specific DNA-binding activity was demonstrated by using electrophoretic mobility shift assay in vitro. This effect of mu-calpain was inhibited by ALLnL and calpastatin and not by lactacystin. In fact, we found that mu-calpain efficiently degraded I kappa B alpha. Furthermore, our Western blotting analysis has revealed that mu-calpain cleaves I kappa B alpha at its N-terminal and C-terminal regions that were previously reported to be involved in the interaction with NF-kappa B p65. These observations indicate that in monocyte/macrophage cells calcium signaling is involved in NF-kappa B activation through activation of calpain and thus calpain inhibitors may be effective in inhibiting the activation of latently infected HIV.

Solitary Intraperitoneal Recurrence of α-Fetoprotein-Producing Gastric Carcinoma : Report of a Case

AbstactA solitary recurrence of gastric carcinoma in the peritoneal cavity is extremely rare. We herein present a case of solitary intraperitoneal recurrence in a patient with α-fetoprotein (AFP)-producing gastric carcinoma. As far as we can determine, this is the first report of such a form of recurrence in a patient with gastric carcinoma who underwent a successful resection. A review of our eight patients who had AFP-producing gastric carcinoma showed a frequent association with hepatic metastasis and a poor prognosis as has been reported previously. Our patient received intra-arterial chemotherapy with low-dose cisplatin and 5-fluorouracil to prevent hepatic recurrence, but eventually developed multiple hepatic metastases after ceasing this therapy. Therefore, adjuvant intra-arterial chemotherapy may have altered the site of first recurrence in this patient.

Arterial infusion therapy with low-dose cisplatin and continuous 5-fluorouracil for isolated hepatic recurrence of gastric carcinoma

Abstract Patients with metachronous liver metastasis after curative resection of gastric carcinoma generally have a poor prognosis, even when recurrence is confined to the liver. We report a patient in whom hepatic arterial infusion therapy with bolus low-dose cisplatin (CDDP) and continuous 5-fluorouracil (5-FU) was effective against large metastases confined to the liver. An 83-year-old man was admitted with huge liver metastases from gastric carcinoma. Intra-arterial bolus injection of low-dose CDDP (5 mg) and continuous intra-arterial infusion of 5-FU (250 mg/day for 7 days) was started. After four courses of this arterial infusion therapy, computed tomography scans revealed shrinkage of the liver metastases. He was followed-up as an outpatient and continued to receive the arterial infusion therapy once every 4 weeks. Throughout the course of the chemotherapy, a partial response of the liver metastases was maintained. The patient had an improved quality of life after starting the chemotherapy, and he survived for 16 months from the commencement of the therapy. Arterial infusion therapy with bolus low-dose CDDP and continuous 5-FU may be recommended for patients with isolated hepatic recurrence of gastric carcinoma.