Daugaard et al showed that ectopic expression of LEDGF p75 protected cancer cells against the LMP inducing agents siramesine and doxoru bicin. Our data showed that ectopic overexpression of LEDGF p75 attenuated DTX induced cytotoxicity and LMP but had no effect on TRAIL induced cell death. Over expression of LEDGF p75 also attenuated DTX induced death in RWPE 2 cells but was not effective against TRAIL and STS. This suggested that LEDGF p75 could be a selective inhibitor of cell death, caspase dependent or independent, associated with LMP. Interest ingly, LEDGF p75 overexpression in PC3 cells failed to prevent DTX induced multinucleation, suggesting that DTX induced mitotic catastrophe is not coupled to LMP.
The mechanisms by which LEDGF p75 promotes lyso somal stability are presently unknown, although the avail able evidence suggests that this protein may protect cells against oxidative stress by transcriptionally activating stress and antioxidant genes that reduce intracellular ROS. A recent study showed that LEDGF p75 physically interacts with the oncogenic transcription fac tor menin and the MLL histone methyltransferase to acti vate cancer associated genes and promote leukemic transformation. Our group is currently exploring interactions between LEDGF p75 and various transcrip tion factors to determine if this proteins ability to pro mote chemoresistance is associated with its capacity to form protein complexes required for transcriptional acti vation of protective genes. Conclusion This study underscores the ability of DTX to induce con comitantly caspase dependent and independent death pathways in prostate cancer cells.
Our data also point to LEDGF p75 as a potential contributor to prostate cancer cell resistance to DTX induced LMP and cell death in vitro. The upregulation of stress and antioxidant genes is emerg ing as a mechanism associated with tumor chemoresist ance. It remains to be investigated if LEDGF p75 overexpression in human prostate tumors contributes to the upregulation or activity of stress redox genes associ ated with cancer progression and chemoresistance. If this turns out to be the case, LEDGF p75, its protein GSK-3 interact ing partners, and its target genes might become attractive candidates for molecular targeting, in combination with DTX and other drugs, in the treatment of HRPC.
Background The mammalian genomes encode four members of the JAK family of protein tyrosine kinases, including JAK1, JAK2, JAK3, and TYK2. In particular, JAK3 is pre ferentially expressed in lymphoid cells and mediates sig nals through gc shared by receptors for IL 2, IL 4, IL 7, IL 9 and IL 15, indicating the crucial role of JAK3 in T cell development and the homeostasis of the immune system. Consistent with this observation, human or animals lacking either JAK3 or gc expression suffer from severe combined immunodeficiency disease character ized by the absence of T and NK cells and the presence of non functional B cells.
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