Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumour progression and therapy resistance in squamous cell carcinoma of the skin (SCC) is strongly associated with resistance to intrinsic mitochondrial apoptosis. We thus investigated the role of various anti-apoptotic Bcl-2 proteins for apoptosis protection in SCC using the BH3 agonist ABT737 that can overcome multidomain Bcl-2 protein protection. Sensitive SCC cells underwent rapid loss of mitochondrial membrane potential (MMP), subsequent apoptosis concomitant with caspase-3 activation and an early release of mitochondria-derived cytochrome c and smac/DIABLO. In contrast, ABT737 resistance in subsets of SCC cells was not explained by XIAP, important for protection from DR-induced apoptosis in SCC. Of note, ABT737 did not prime SCC cells to DR-induced apoptosis. Interestingly, the ratio of Mcl-1 and Noxa determined sensitivity to ABT737: loss of Mcl-1 rendered resistant cells sensitive to ABT737, whereas loss of Noxa promoted resistance in sensitive cells. In line, suppression of Mcl-1 by the pan-Bcl-2 inhibitor Obatoclax or overexpression of Noxa rendered resistant SCC cells sensitive to BH3 mimetics. Our data indicate that targeting of the Mcl-1/Noxa axis is important to overcome resistance to mitochondrial apoptosis in SCC. Therefore, combination treatment of ABT737 or derivatives with Mcl-1 inhibitors, or inducers of Noxa, may represent a novel option of targeted therapy in metastatic SCC of the skin.
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PMID:The ratio of Mcl-1 and Noxa determines ABT737 resistance in squamous cell carcinoma of the skin. 2574 98

Cutaneous squamous cell carcinoma (cSCC) is a common malignant tumor. Mammary serine protease inhibitor (Maspin), a member of serpin family, has been reported as a tumor suppressor in various carcinomas. In this study, we detected the expression level of Maspin in cSCC tissues by real-time PCR and western blotting, and found that Maspin was downregulated in the cSCC tissues compared with the adjacent normal tissues. Moreover, Maspin was stably overexpressed in A431 cells, and CCK-8 assay, colony formation assay, Transwell assay, Hoechst staining and western blotting were carried out to detect the growth, proliferation, invasion, cell cycle and apoptosis of A431 cells. The results revealed that overexpression of Maspin inhibited growth, proliferation, invasion and cell cycle G1/S/G2 transition and enhanced apoptosis of A431 cells. The pro-apoptotic protein cleaved caspase-3, poly(ADP-ribose) polymerase (PARP) and Bax increased, and the anti-apoptotic protein Bcl-2 decreased after Maspin overexpression. Therefore, we demonstrated that Maspin suppressed growth, proliferation and invasion by delaying cell cycle transition and promoting apoptosis in cSCC cells, which may provide new insights for the clinical diagnosis and therapy of cSCC.
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PMID:Maspin suppresses growth, proliferation and invasion in cutaneous squamous cell carcinoma cells. 2840 81