Identification of Novel Retinoid Targets in Prostate Cancer
Abstract
Retinoids have shown promise for the chemoprevention and treatment of prostate cancer. However except for the efficient treatment of acute promyelocytic leukemia and certain skin disorders most natural and synthetic retinoids have failed in clinical trials because of toxicity and limited activity. Retinoids exert their biological activity mainly upon binding and activation of the nuclear retinoid receptors (RARs and RXRs). Novel synthetic retinoid-related molecules (RRMs) that show selective activity towards RARala (MX3350-1 CD2325) or function as RAR antagonists (MX781) have been discovered that elicit strong anticancer activity and represent promising leads for the chemoprevention and treatment of prostate cancer. These RRMs induce apoptosis independently of RARs; instead they bind to other cellular proteins to elicit profound effects on the cell signaling events that lead to inhibition of cell growth and induction of programmed cell death. The cellular targets that mediate RRM-anticancer activity are unknown and the molecular mechanism of RRM action is currently under extensive investigation. Our goals were to identify genes that mediate RRM anticancer activity upon selection of Genetic Suppressor Elements (OSE) that confer resistance to RRM treatment in prostate cancer cells. OSE expression is expected to inhibit RRM-induced apoptosis by blocking the function of key genes that are critical for the anticancer activity of RRMs. After standardizing the experimental conditions to achieve optimal retrovirus production and infection of RC3 cells we have performed several screenings in the presence of toxic amounts of MX781 and MX3350-i. OSEs have been subsequently rescued from surviving cells by POR amplification using primers specific for the OSE library followed by identification by DNA sequencing. Several genes many of them with biological functions unrelated to apoptosis have been identified as potential candidates of interest for functional validati
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2006
- Accession Number
- ADA463912
Entities
People
- F. J. Piedrafita