RESUMO
The pancreatic cancer remains a fatal disease for the majority of patients. Cisplatin has displayed significant cytotoxic effects against the pancreatic cancer cells, however the underlying mechanisms remain inconclusive. Here, we found that cisplatin mainly induced non-apoptotic death of the pancreatic cancer cells (AsPC-1 and Capan-2), which was associated with a significant p53 activation (phosphorylation and accumulation). Further, activated p53 was found to translocate to mitochondria where it formed a complex with cyclophilin D (Cyp-D). We provided evidences to support that mitochondrial Cyp-D/p53 complexation might be critical for cisplatin-induced non-apoptotic death of pancreatic cancer cells. Inhibition of Cyp-D by its inhibitor cyclosporine A (CsA), or by shRNA-mediated knockdown suppressed cisplatin-induced pancreatic cancer cell death. Both CsA and Cyp-D knockdown also disrupted the Cyp-D/p53 complex formation in mitochondria. Meanwhile, the pancreatic cancer cells with p53 knockdown were resistant to cisplatin. On the other hand, HEK-293 over-expressing Cyp-D were hyper-sensitive to cisplatin. Interestingly, camptothecin (CMT)-induced pancreatic cancer cell apoptotic death was not affected CsA or Cyp-D knockdown. Together, these data suggested that cisplatin-induced non-apoptotic death requires mitochondria Cyp-D-p53 signaling in pancreatic cancer cells.
Assuntos
Morte Celular , Cisplatino/farmacologia , Ciclofilinas/metabolismo , Mitocôndrias/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Linhagem Celular Tumoral , Peptidil-Prolil Isomerase F , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Necrose , Fosforilação , Transdução de SinaisRESUMO
OBJECTIVE: To establish transplanted models of VX2 tongue carcinoma in rabbits by three methods and compare these models. METHODS: After establishment of VX2 tumor-bearing rabbits, 72 New-Zealand white rabbits were randomly divided into 3 groups. Intact tumour tissue, modified tumour cell suspension, tumour cell suspension were respectively injected into the middle-third lateral border of the tongues of rabbits in 3 groups to induce transplanted VX2 tongue carcinoma. The histological features, the tumour-take rates and the metastasis rates of the 3 models were observed. RESULTS: The tumour-take rate of 3 models were 83.3%, 91.7% and 33.3% respectively; the lymph node metastasis rates were 71.4%, 100.0% and 37.5% respectively; the lung metastasis rates were 35.7%, 81.3% and 0 respectively. The histological features of the transplanted VX2 tongue carcinoma of 3 models were all consistent with those of moderately differentiated carcinoma. CONCLUSION: The biological properties of the transplanted VX2 tongue carcinoma of 3 models is much alike to tongue carcinoma in humans. The model established with modified tumor cell suspension is considered to be more suitable for tongue cancer study.