The PSA Controversy Again

In view of this week's vote on health care and my ongoing concern regarding the current bill which empowers some corpulent marginally educated GS-9 to decide who gets what procedure, and yes that means lives or dies, via the rubric of comparative clinical effectiveness, I will present an interesting update on the PSA issue.

You see, in the past year we have had all types of folks saying that PSA is ineffective, breast mammograms do not work, and that "watchful waiting", the euphemism of just sending you home, has reached the top of the list for the current Administration. Somehow they think that we know everything and that we can now make decisions. Yet every week something new comes out.

Let me address the PSA issue in the context of a paper which came out last week. The question is why does the PSA increase and more importantly why with PCa does the % Free PSA drop. This paper gives some insight.

In the normal course of prostate cell homeostasis, PSA is produced by the binding of Testosterone to the ligand on the luminal cell and the resulting transformation to DHT and its binding to the Androgen Receptor which acts in turn as a transcription factor for PSA. PSA exists mostly in complexed and inactive form; bound to alpha 2 macroglobulin and alpha 1 antichymotrypsin. 40% of the bound is with alpha 2 macroglobulin. Half-life PSA is 2.2-3.2 days. The baseline may takes weeks to return to normal after certain procedures.

We show this process below (See Feldman and Feldman, 2001):

 

In the above the PSA is released and then is free, it may bind with alpha 2 macroglobulin or with alpha 1 antichymotrypsin. In a benign configuration there is generally 35% of the PSA remaining free and unbound.

Now in a recent paper by Misra et al (2011) they discuss the impact of GRP78 in cancerous cells. In a recent write-up of the work the authors state (see Gore, Eureka):

Using human prostate cancer cells in a laboratory culture, the team found that an antibody reacts with a cell surface receptor called GRP78 on the cancer cells to produce more PSA. The PSA arises inside of the cancer cell and then moves outside of the cell, where it can bind with the same antibody, called alpha2-macroglobulin (α2M).

The PSA forms a complex with the antibody that also binds to the GRP78 receptor, and that activates several key pathways which stimulate cancer cell growth and cell movement and block cell death.

The study bolsters the case for measuring PSA as a marker of tumor progression, as well as for monitoring for α2M antibody levels.

That is the release of GRP78 enforces the release of PSA, bound to alpha-2-M which increases PSA total and reduces PSA free. The GRP78 is then an added marker for excess cell growth, and thus a putative marker for PCa and putatively PSA total and percent free than has substantially increased significance for monitoring PCa.

Also this is a positive feedback loop, the link to the enhancement of Akt then is an enhancement of cell proliferation and growth even with the negative influence of PTEN if present.

GRP78, a well characterized chaperone in the endoplasmic reticulum, is critical to the unfolded protein response. As Lee (2007) states:

The glucose-regulated protein GRP78, also referred to as BiP (immunoglobulin heavy-chain binding protein), was discovered in the late 1970s together with GRP94 and GRP58 as cellular proteins induced by glucose starvation. Residing primarily in the ER, GRP78 belongs to the HSP70 protein family, which plays critical roles in the stress of oncogenesis.

In addition to facilitating proper protein folding, preventing intermediates from aggregating, and targeting misfolded protein for proteasome degradation, GRP78 also binds Ca2+ and serves as an ER stress signaling regulator. In nonstressed cells, GRP78 binds to ER transmembrane sensor proteins PERK, IRE1, and ATF6 and maintains them in an inactive form. When unfolded proteins pull GRP78 away from them, these pathways are activated, sending signals to the nucleus to trigger the UPR.

As Pootrakul et al state:

The glucose-regulated proteins (GRP) were initially identified as such in transformed chick embryo fibroblasts growing in glucose-deprived medium. The most well studied member of the GRP family is Grp78, a 78-kDa protein also recognized as immunoglobulin heavy-chain binding protein (BiP).Normal functions of Grp78, which resides in the endoplasmic reticulum (ER) lumen, include proper folding and assembly of other polypeptides leading to formation of functional proteins, retention of unassembled precursors to the ER, targeting mis-folded protein for degradation, ER Ca2+ binding, and the regulation of trans-membrane ER stress inducers. 

The involvement if Grp78 in enhanced cell survival is suggested by the remarkable elevation of GRP78 transcription rates under various stress conditions.

Recently, Grp78 has been shown to directly interact with intermediates of the apoptotic pathway, blocking caspase activation, where Grp78induction results in increased cell survival and inhibition of apoptosis.

More recently, it has been identified on the cell surface, where it has many roles. On cancer cells, it functions as a signaling receptor coupled to proproliferative-antiapoptotic and promigratory mechanisms.

In the current study, Misra et al (2011) demonstrate that:

1. Ligation of prostate cancer cell surface GRP78 by its natural ligand, activated α₂-macroglobulin (α₂M*),

2. Results in a 2–3-fold up-regulation in the synthesis of prostate-specific antigen (PSA).

3. The PSA is secreted into the medium as an active proteinase, where it binds to native α₂M.

4. The resultant α₂M·PSA complexes bind to GRP78, causing a 1.5–2-fold increase in the activation of MEK1/2, ERK1/2, S6K, and Akt,

5. Which is coupled with a 2–3-fold increase in DNA and protein synthesis.

PSA is a marker for the progression of prostate cancer, but its mechanistic role in the disease is unclear. The present studies suggest that PSA may be involved in a signal transduction-dependent feedback loop, whereby it promotes a more aggressive behavior by human prostate cancer cells. We demonstrate this below:

Thus what does this tell us? Simply, there is now a well defined mechanism for PSA and % Free PSA and we can relate it to the pathways for PCa. This further strengthens the use of PSA despite what the Administration may say. Science is a strange thing at times, really!

References:

Feldman, B., D., Feldman, The Development of Androgen Independent Prostate Cancer, Nature Reviews Cancer, Vol 1, 2001, pp 34-45.

Gore, M., Eureka, 2011.

Lee, A., GRP78 Induction in Cancer, Can Res 2007 pp 3946-3499.

Misra, U., Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop: A Role for Secreted Prostate-Specific Antigen, Jrl Bio Chem 2011, pp 1248-1259.

Pootrakul, L., et al, Expression of Stress Response Protein Grp78 is Associated with the Development of Castration Resistant Prostate Cancer. Hum Can Bio 2006 pp 5987-5993.