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nce tumor growth and survival . Activated glycogen synthase kinase 3? serine 9 phosphorylation is also needed for tumor cell survival and anti apoptosis . Based on that the present study, enhanced expression of pERK, GSK 3b and CDK2 in G3 expressing breast cancer cells favored cell survival and growth even in serum free of charge conditions or when cultured within the environment Celecoxib of applied chemotherapeutic reagents. In specific, versican G3 enhanced cell survival was prevented by both selective EGFR inhibitor AG 1478 and selective MEK inhibitor PD 98059 by means of mechanisms blocking G3 activated expression of pERK and GSK 3 b . Versican G3 expressing breast cancer cells demonstrated enhanced cell survival in serum free of charge medium and chemotherapy by activating EGFR ERK signaling and its downstream pathway proteins CDK2 and GSK 3b .
To validate the roles of versican and G3 domain in modulating breast cancer cell apoptosis Celecoxib in response to applied chemotherapy, we transfected tumor cells with anti versican siRNA also as by linking versican G3 domain with versican 39 UTR that reduces versican and G3’s functionality. Prior Alogliptin study demonstrated that non coding versican 39 UTR significantly down regulates G3 protein expression . Concordantly, we observed that both anti versican siRNA and G3 UTR construct decreased G3 enhanced anti apoptosis when treated with Doxorubicin and Epirubicin. The EGFR signaling pathway is indispensable for cell cycle progression whilst it may also efficiently enhance apoptosis .
Even though activation with the EGFR ERK signaling pathway is commonly deemed to result in cell survival , there's evidence that in certain conditions it may also transmit pro apoptotic signals . Along with its effects on proliferative capacity and increasing apoptotic resistance, over expression of versican is often accompanied by selective sensitization to apoptosis . Whereas V1 HSP transfected cells have shown resistance to apoptosis, they also have grow to be significantly sensitized to other apoptotic stimuli, such as UV radiation, chemotherapeutics, hypoxic mimetics, and conjugated linoleic acid. Elevated resting levels with the tumor suppressor p53 play a key function in inducing apoptosis in response to a variety of detrimental events, such as DNA damage, hypoxia, and telomere erosion . In this study we also noted that versican G3 expressing breast cancer cells showed enhanced apoptosis when treated with certain chemical substances, for example C2 ceramide and Docetaxel.
In this scenario, chemotherapy induced apoptosis may be enhanced because of the recruitment of enhanced efficiency of cellular signaling. We identified that although high levels Alogliptin of pERK were observed in G3 expressing cells when treated with these chemical substances, a single with the other EGFR down stream proteins p SAPK JNK was significantly activated. The pro death or prosurvival function of ERK can have both, survival or cell death activities . Literature supports an effect of breast cancer cells on cellular SAPK JNK activation in a pro death capacity but a function of pro survival was also observed . In our study, both p ERK and p JNK was expressed in high levels within the G3 expressing cells immediately after treatment with C2 ceramide and Docetaxel.
To establish which factor played a key function in versican G3 enhanced cell apoptosis, Celecoxib we co treated the G3 expressing cells with chemical substances and AG 1478, PD 98059 or SP 600125; we observed that G3 key mediators of mammalian cell apoptosis , which consequently led to cell death. This hypothesis was supported by the fact that both AG 1478 and SP 600125 blocked G3 enhanced expression of Caspase 3 and cell apoptosis whilst PD 98059 did not. Reduction in expression of versican and versican G3 domain by anti versican siRNA and G3 39UTR construct significantly decreased G3 enhanced effects on cell apoptosis induced by chemotherapeutics and confirmed that versican G3 expressing breast cancer cells promoted cell apoptosis induced by chemotherapeutics by means of G3 dependant mechanisms.
An interesting observation of our study would be the apparent dual roles of versican G3 domain in modulating breast cancer cell resistance to chemotherapy and EGFR targeting therapy. EGFR signaling appears essential to the sensitivity or resistance of versican expressing breast cancer cells to chemotherapy. The apoptotic effects of chemotherapeutics Alogliptin on these cells depend on the activation and balance of EGFR signaling and its effects downstream. Certain chemical substances for example Doxorubicin and Epirubicin activate versican G3 expressing cells’ endogenous EGFR ERK GSK 3b signaling promoting chemical resistance whilst other people chemical substances appear to enhance these cells’ sensitivity to chemotherapy by means of elevated expression of EGFR JNK signaling and subsequent effects on apoptosis. Our study has identified a key EGFR down stream proteins, GSK 3b that appears critically important as a regulatory check point within the balance of apoptosis and anti apoptosis . Results demonstrated that G3 expressing cells enhanced GSK 3b expression when treated