Novel insights in cell cycle dysregulation during prostate cancer progression

Abstract

Prostate cancer (CaP) remains the second leading cause of cancer deaths in Western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators and address challenges and limitations in the approaches modulating their action for CaP treatment.

Keywords: androgen receptor; castration; proliferation; treatment resistance.

Figure 1.. Overview of cell cycle progression.

The cell cycle is regulated by the activity of cyclin-dependent kinases (CDKs), which are controlled by the availability of their binding partners from the cyclins family. During G1, Cyclins D and E are overexpressed, complex with their partner CDKs and phosphorylate RB. Phosphorylated RB releases E2F transcription factors which in turn activate genes required for S phase entry. Inhibition of RB is maintained by cyclin B-CDK1 during S-G2 and G2-M transitions. Cells exist the M phase after dephosphorylation of RB, which binds and inhibit E2F. During all cell cycle phases, CDK inhibitors (i.e p27, p21) govern proper transition by inhibiting CDKs function. RP, Restriction point, RB, Retinoblastoma.

Figure 2.. Schematic overview of sites of AR phosphorylation by cell cycle regulators.

Numbers indicate the AR amino acid residue that is phosphorylated. The functional implication of phosphorylations at these residues is indicated, and the cell cycle regulator responsible for phosphorylations at specific residues across AR’s functional domains is listed. Please note that the (updated) amino acid numbering system used in this figure and the associated manuscript section is based on NCBI reference sequence NM_000044.2. AR, Androgen Receptor; NTD, N-terminal transactivation domain; DBD, DNA-binding domain; HR, hinge region; LBD, ligand binding domain; AurA, Aurora kinase A; CDK, cyclin dependent kinase; PIM1, proto-oncogene serine/threonine-protein kinase; PTEN, Phosphatase and tensin homolog; T, phosphorylation impacts AR transcription function; S, phosphorylation impacts AR stability; L, phosphorylation impacts AR localization; G, phosphorylation impacts CaP growth.

Figure 3.. Overview of drugs targeting cell cycle regulators and in clinical trials for CaP treatment.

Targets for drugs are shown in italics between brackets. Data to generate the figure was obtained by searching the clinicaltrial.gov site for all prostate studies using the (cell cycle regulator) target as keyword. CDKs, cyclin dependent kinases; AKT, Protein kinase B; ATR, Ataxia telangiectasia and Rad3 related; CHK, checkpoint kinase; DNA-PK, DNA-dependent protein kinase; WEE1, G2–M cell-cycle checkpoint kinase; Aurora A, serine/threonine kinase; KSP/Eg5, Kinesin spindle protein; PLK1, polo-like kinase 1; *, Multi-kinase inhibitor.