Integrin α5ß1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma.

Integrin α5ß1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5ß1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5ß1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5ß1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5ß1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5ß1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5ß1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5ß1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

[Immunohistologic detection of pepsin and gastricsin in carcinoma of the stomach]. / Imunohistologický prukaz pepsinu a gastricsinu v karcinomech zaludku.

Immunohistological tests for pepsin and gastricsin were carried out in bioptic samples of 51 patients with carcinoma of the stomach. Pepsin was detected in only 2 cases (4%), gastricsin in 26 patients (55%). Compared to the histological picture, the rate of incidence of gastricsin showed no difference between the intestinal and diffuse types of this tumour. In all examined cases, only gelatinous carcinomas were negative. Nor were any differences found in the cardia, the body or antrum. Surprisingly, these enzymes were found in the cytoplasma of neutrophylic granulocytes in the inflammatory infiltrate of the mucosal and tumorous stroma. Intestinal metaplasia of the epithelium was always negative even in the neighbourhood of positive tumours. The detected changes are evidence against the possibility of different histogenesis of the diffuse and intestinal forms of carcinoma of the stomach as well as against the possibility that intestinal metaplasia in a chronic inlammation of the stomach could be regarded as a direct first stage of the intestinal form of carcinoma of the stomach. In cases of metastases of unknown origin, pepsin and gastricsin cannot serve as markers due to their insufficient organ and cell specificities.