Dysfunction of apoptotic signal transduction pathway of malignant

Dysfunction of apoptotic signal transduction pathway of malignant cells can also cause drug resistance. For example, down-regulation of pro-apoptotic genes such as Bax and Fas/FasL

and up-regulation of anti-apoptotic genes such as Bcl-2 has been involved in drug resistance. Fas, a 45 kDa type I transmembrane protein, is expressed on cell membranes of varieties of normal cells and malignant cells including lung cancer cells [2, 3]. Its ligand, FasL, is expressed Eltanexor on the cell membrane of activated T lymphocytes and some malignant cells [4, 5]. After trimerization of Fas on the cell membrane by extracellular FasL [6], Fas-associated death domain (FADD) and caspase 8 bind to the intracellular death domains of Fas and induce a death signal in the cells [7], leading to the activation of a cascade of caspases and eventually to cell death. Since FasL can induce apoptosis in Fas-expressing PD0332991 order malignant cells, the Fas/FasL system plays an important role in T cell-mediated cytotoxic

reaction and malignant cell-mediated autocrine suicide or selleck screening library paracrine death against malignant cells. On the other hand, malignant cells can avoid being killed by down-regulating Fas expression. It has been demonstrated that cisplatin-resistant lung cancer cells express low level of Fas, and correspondingly, their apoptosis decreases significantly. Some reports have correlated multidrug resistance (MDR) with the decreased Fas expression and resistance to Fas-mediated apoptosis. Fas-resistant

cells were resistant to chemotherapeutic drug treatment, which is presumably due to the disruption of pathways responsible for the induction Forskolin datasheet of cell death by chemotherapeutic drugs [8]. Many agents can induce the expression of Fas, and thus promote the apoptosis of malignant cells. Cisplatin can enhance some solid tumors or leukaemic cell surface expression of Fas [9–11] via the activation of the acid sphingomyelinase (aSMase) and the generation of ceramide at the plasma membrane. Up-regulating the expression of melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) can enhance the expression of Fas activated by cisplatin. Cisplatin can also enhance MDA-7/IL-24 toxicity via activation of the extrinsic pathway and de novo ceramide synthesis [12]. Bruno Segui et al proposed that it might be a way to treat cancer by enhancing the expression of Fas and promoting the apoptosis of tumor cell [13]. But in cisplatin-resistant human squamous cell carcinomas of the head and neck (SCCHN) cells, although the expression of Fas was enhanced by cisplatin or IFN-γ, the cisplatin sensitivity cannot be restored by agonistic Fas-antibodies [14].

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