Prostate cancer cells rely on
androgen receptor (AR) for proliferation and survival. Therefore, curing
prostate cancer will require elimination of AR. Although
androgen is the natural
ligand that activates AR, AR activity is also subject to regulation by
growth factor/
growth factor receptor-stimulated signaling pathways that control the cell cycle.
Cell cycle regulatory proteins and
protein kinases in signaling pathways affected by
growth factors can lead to AR activation in the absence of
androgen. While downstream signaling
proteins such as
cyclins,
cyclin-dependent kinases (CDKs), and pRB can modulate AR activity, upstream signaling pathways involving
protein kinases such as
mitogen-activated protein kinases,
protein kinase A, and
protein kinase B/Akt can affect post-translational modification of AR to affect not only AR function but also AR stability.
Calcium and
calmodulin (CaM), essential for proliferation and viability of a number of cells, including
prostate cancer cells, play an important role in AR expression, stability, and function. CaM affects AR partly by interacting directly with AR and partly by activating
protein kinases such as Akt and
DNA-PK that can phosphorylate AR. The
ubiquitin/
26S proteasome pathway responsible for timely destruction of
cell cycle regulatory proteins whose levels impede cell cycle progression also induces AR expression by activating
NF-kappaB, and promotes AR activity by participating in the assembly of an AR transcription complex.
Maspin, a
serine protease inhibitor that is known mostly for its role as a
tumor suppressor can also regulate AR intracellular localization and function by competing with AR for binding to the chaperone
protein Hsp90 and
co-repressor HDAC1, respectively. This perspective reviews the experimental evidence implicating these diverse cellular processes in AR expression, stability, and/or function, and presents a rationale for disrupting these cellular processes as a viable option for the treatment of both the
hormone-sensitive and the
hormone-insensitive
prostate cancer.