Parthenolide and STAT: It is previously discussed that the activation of STAT directs to cell proliferation, cell migration, transformation, apoptosis, cellular differentiation, adhesion, fetal development, inflammation, and immune response. In normal homeostasis, STAT tyrosine phosphorylation is short-term, lasting from 30 minutes to several hours, where as in numerous cancer cell lines and primary tumors it is in contrary to that of normal homeostasis. It takes place due to the deregulation of positive effectors of STATs activation, such as upstream tyrosine kinases (JAK, TYK), or repression of negative regulators of STATs phosphorylation, e.g. phosphatases, suppressors of cytokine signaling or protein inhibitors of activated STATs [47, 48].
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All MAPKs are activated by dual phosphorylation of threonine and tyrosine motifs within the sub-domain VIII of activation loop. Once activated, they translocate to the nucleus and phosphorylate target transcription factors, such as c-Jun. JNK involved in apoptosis, neurodegeneration, cell differentiation, proliferation and inflammatory conditions [50]. Won et al. (2004) showed that PN inhibited JNK activation and led to UVB-induced apoptosis of JB6 murine epidermal cells [51]. But Zhang et al. (2004) demonstrated that inhibition of NF-kappaB activation and sustained JNK activation contribute to the sensitization of PN effect on TNF- induced apoptosis in human cancer cells [39]. The authors reported that PN sensitizes human nasopharyngeal carcinoma (CNE1) cells to TNF-α induced apoptosis. Tang et al. (2001) and Varfolomeev et al. (2004) concluded that sustained JNK activation had resulted from NF-κB inhibition [52, 53]. Furthermore, it downregulates the phosphorylated form of NF-κB, p38MAPK, and ERK1/2 protein level [Popiolek-Barczyk et al., 2015 Neural Plast]. Based on the literature data, it is evident that in normal cells, PN protects cells from apoptosis whereas in cancer cells, it supports apoptotic cell death
All MAPKs are activated by dual phosphorylation of threonine and tyrosine motifs within the sub-domain VIII of activation loop. Once activated, they translocate to the nucleus and phosphorylate target transcription factors, such as c-Jun. JNK involved in apoptosis, neurodegeneration, cell differentiation, proliferation and inflammatory conditions [50]. Won et al. (2004) showed that PN inhibited JNK activation and led to UVB-induced apoptosis of JB6 murine epidermal cells [51]. But Zhang et al. (2004) demonstrated that inhibition of NF-kappaB activation and sustained JNK activation contribute to the sensitization of PN effect on TNF- induced apoptosis in human cancer cells [39]. The authors reported that PN sensitizes human nasopharyngeal carcinoma (CNE1) cells to TNF-α induced apoptosis. Tang et al. (2001) and Varfolomeev et al. (2004) concluded that sustained JNK activation had resulted from NF-κB inhibition [52, 53]. Furthermore, it downregulates the phosphorylated form of NF-κB, p38MAPK, and ERK1/2 protein level [Popiolek-Barczyk et al., 2015 Neural Plast]. Based on the literature data, it is evident that in normal cells, PN protects cells from apoptosis whereas in cancer cells, it supports apoptotic cell death