Cyclin degradation for cancer therapy and chemoprevention

Abstract

Cancer is characterized by uncontrolled cell division resulting from multiple mutagenic events. Cancer chemoprevention strategies aim to inhibit or reverse these events using natural or synthetic pharmacologic agents. Ideally, this restores normal growth control mechanisms. Diverse classes of compounds have been identified with chemopreventive activity. What unites many of them is an ability to inhibit the cell cycle by specifically modulating key components. This delays division long enough for cells to respond to mutagenic damage. In some cases, damage is repaired and in others cellular damage is sufficient to trigger apoptosis. It is now known that pathways responsible for targeting G1 cyclins for proteasomal degradation can be engaged pharmacologically. Emergence of induced cyclin degradation as a target for cancer therapy and chemoprevention in pre-clinical models is discussed in this article. Evidence for cyclin D1 as a molecular pharmacologic target and biological marker for clinical response is based on experience of proof of principle trials.

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

“…In line with our findings above, BMP4 and CDKN1B were increased, which reflected the activation of endogenous TGF-b signaling (Lecanda et al, 2009 Figures 5A and B), which is consistent with published results (Ellenrieder et al, 2001;Hamada et al, 2007). Furthermore, BCL2L1, CCND1 and MYC, which are survival pathway-related genes, were upregulated underscoring the importance of prosurvival signals during EMT (Biliran et al, 2005;Freemantle et al, 2007;Barbie et al, 2009). EGR1, which represents a mitogenic pathway, was downregulated, consistent with the observed increased expression of the cell-cycle inhibitor p21 (Lim et al, 2008).…”

C/EBPδ targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression

“…Indeed, specific ablation of cyclin D1 is a validated strategy against breast cancer (22,41). Many structurally unrelated chemotherapeutic compounds down-regulate cyclin D1, and cyclin D1 expression can be a surrogate marker of therapeutic efficacy (22).…”

“…Many structurally unrelated chemotherapeutic compounds down-regulate cyclin D1, and cyclin D1 expression can be a surrogate marker of therapeutic efficacy (22). However, the exact mechanism(s) by which these compounds act on cyclin D1 proteins is largely unknown (22,41). Specific knowledge about the various modalities of cyclin D1 regulation will be critical to understand why some cell lines or cancers are responsive while others are not and how to manage cancers with mutations and, therefore, resistance against certain therapeutic agents.…”

PP2ACdc55regulates G1cyclin stability

“…dephosphorylates the G 1 cyclin, Cln2, thus maintaining its stability, while SCF Grr1 is responsible for initiating phosphorylationdependent ubiquitylation and degradation, both of which are necessary for the inactivation of G 1 cyclin-cdk activity and subsequent activation of a cyclin-cdk activity required for G 2 -M. 9 As mammalian cyclin D1 is overexpressed in human cancers, 5,48,49 and its stability is associated with defects in SCF activity, 50 targeting PP2A through inhibiting its activity may represent a plausible therapeutic for cancer treatment.…”