This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Retinoids are vitamin A derivatives which have preventative and therapeutic value in thetreatment of some cancers. The mechanism of action of retinoids is thought to bemediated, at least in part, by interaction with nuclear receptors resulting in modula tion ofgene transcription. Recent studies suggest that retinoids enhance cellular reactive oxygenspecies (ROS) formation, particularly superoxide anion. Superoxide and its dismutationproduct, hydrogen peroxide, are signaling molecules; therefore, alte r ation of redox statusby retinoids may contribute to modulation of differentiation genes. Manganesesuperoxide dismutase (MnSOD) is an essential, mitochondrial localized primaryantioxidant which has been shown to enhance cellular differentiation. The o verall goal ofthis project is to investigate the link between MnSOD and all-trans retinoic acid (ATRA)in a model of neuroblastoma differentiation. The hypothesis to be tested is thatupregulation of MnSOD is an essential, initial transcriptional event i n ATRAdifferentiation of neuroblastoma which subsequently enhances mitochondrialfunction, resulting in chemoresistance. Using an ATRA responsive neuroblastoma cellline, SK-N-SH, the hypothesis will be tested in four specific aims.
Specific aim 1 wil ld et ermine if NFk:B activation is responsible for MnSOD induction in response toATRA.
Specific aim 2 will determine if ROS, generated as a result of ATRAadministration, contribute to upregulation of MnSOD.
Specific aim 3 willdetermine if MnSOD is e s sent ial to ATRA dependent differentiation in the SK-NSHcell line.
Specific aim 4 will determine if MnSOD protects cells from cisplatininducedapoptosis as a result of ATRA administration. The basis of this project is todelineate the link between ATR A m ediat ed d ifferentiation of neuroblastoma and MnSODupregulation. This proposal will generate data which will determine MnSOD''s role asessential to the differentiation process and/or protective against chemotherapeutic agentswhich initiate mitoch o n dri al med iated programmed cell death..coa
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