Amino acid deprivation of Chinese hamster ovary cells overexpressing human insulin receptors results in deactivation of p70 S6 kinase (p70) and dephosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), which become unresponsive to insulin; readdition of amino acids restores these responses in a rapamycin-sensitive manner, suggesting that amino acids and mammalian target of rapamycin signal through common effectors. Contrarily, withdrawal of medium amino acids from the hepatoma cell line H4IIE does not abolish the ability of insulin to stimulate p70 and 4E-BP1. The addition of 3-methyladenine (3MA) to H4IIE cells deprived of amino acids inhibited the increment in protein degradation caused by amino acid withdrawal nearly completely at 10 mM and also strongly inhibited the ability of insulin to stimulate p70 and 4E-BP1 at 10 mM. Treatment of H4IIE cells with 3MA did not alter the ability of insulin to activate tyrosine phosphorylation, phosphoinositide 3-kinase, or mitogen-activated protein kinase. In conclusion, the ability of H4IIE cells to maintain the insulin responsiveness of the mammalian target of rapamycin-dependent signaling pathways impinging on p70 and 4E-BP1 without exogenous amino acids reflects the generation of amino acids endogenously through a 3MA-sensitive process, presumably autophagy, a major mechanism of facultative protein degradation in liver.

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Amino acids, especially branched-chain amino acids such as l-leucine, have been shown to regulate activation of p70 S6 kinase and phosphorylation of 4E-BP1 through the mTOR signaling pathway. In our recent study, l-arginine was also shown to activate the mTOR signaling pathway in rat intestinal epithelial cells. l-Glutamine is an amino acid that is required for culturing of numerous cell types, including rat intestinal epithelial cells. In this study, we showed that l-glutamine inhibited the activation of p70 S6 kinase and phosphorylation of 4E-BP1 induced by arginine or leucine in rat intestinal epithelial cells. Although the molecular mechanism of l-glutamine-induced inhibition of the mTOR signaling pathway is still unknown, the presence of this novel signal pathway may indicate that individual amino acids play specific roles for cellular proliferation and growth.

The addition of leucine induced activation of p70 Tk in amino acid-depleted H4IIE cells. Whereas the activation of p70 Tk by leucine was transient, the complete amino acid stimulated p70 Tk more persistently. The effect of leucine on p70 Tk was sensitive to rapamycin, but less sensitive to wortmannin. Using various amino acids and derivatives of leucine, we found that the chirality, the structure of the four branched hydrocarbons, and the primary amine are required for the ability of leucine to stimulate p70 Tk , indicating that the structural requirement of leucine to induce p70 Tk activation is very strict and precise. In addition, some leucine derivatives exhibited the ability to stimulate p70 Tk and the other derivatives acted as inhibitors against the leucine-induced activation of p70 Tk .z 1999 Federation of European Biochemical Societies.

We report seven early gastric cancers in five patients, which arose in the reconstructed gastric tube after radical resection for esophageal cancer. Four of them occurred in the middle gastric tube and three in the distal gastric tube. Three of 5 cases were reconstructed via the retromediastinal route and two via the presternal route. They all were diagnosed by follow-up endoscopy from 8 months to 5 years after esophagectomy. All of them were treated surgically with partial resection of the gastric tube because they were suspected to have invaded the submucosal layer or large enough to be treated with endoscopic mucosal resection (EMR). Histologically, six of seven were diagnosed as well differentiated adenocarcinoma and one as signet ring cell carcinoma. Although one of them died for reasons other than cancer itself, the others are alive and well without any recurrence. Recently, gastric tube cancer after esophagectomy has been increasingly reported to be accompanied with prolongation of survival of esophageal cancer patients. Total or partial gastrectomy is proposed for surgical treatment of gastric tube cancer, but the operating procedure is complicated and invasive, especially in the case of gastric tube reconstructed via the retromediastinal route. Total gastrectomy is much more invasive because it needs re-reconstruction with other organs. Therefore, it is important to detect the lesion in early stages so as to treat it with minimally invasive surgery such as EMR or partial resection. Hence intensive follow up with endoscopy is necessary after resection of esophageal cancer.

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. Basaloid squamous carcinoma of the esophagus is very rare. We report two cases of basaloid squamous carcinoma of the esophagus. Both tumors histologically consisted of solid cell nests with intervening fibromyxoid stroma. In some tumor nests were comprised of pseudoglandular structures containing myxoid matrix, and displayed focal immunoreactivity for laminin. Thoracic esophagectomy with lymph node dissection was followed by intrathoracic esophagogastrostomy in both patients. The patients had uneventful postoperative courses. Regular periodic follow-up showed no evidence of recurrence or metastasis in the 22-month postoperative period.

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