BERKELEY, CA (UroToday.com) - Cancer cells adapt to chronic stress by inducing the expression of GRP78/Bip, a major endoplasmic reticulum (ER) chaperone with anti-apoptotic properties. Recently this protein has been detected on the surface of cancer cells but not in normal tissues and has therefore made it an important molecule for targeted therapy. The surface expression of GRP78/BiP can be used for tracking and imaging tumor cells. It can also be developed for therapy by targeting tumor cells with synthetic chimeric peptides composed of GRP78-binding motifs fused to cell-death-inducing sequences.
A work recently published by our group from the Karlsruhe Institute of Technology in Germany describes a peptidic molecule derived from the cochaperone Bag-1 which, when expressed in prostate cancer cells, binds to GRP78/BiP and inhibits prostate cancer cell growth. The Bag-1 peptide they identified induced cell death without the need for a pro-drug conjugate or fusion with a death-inducing sequence. It has the intrinsic property of inducing cell death and is therefore a unique peptide with a different mode of action. They could specifically show that the identified peptide inhibited growth of xenograft tumor mouse models generated by the injection of 22Rv.1 and LNCaP prostate tumor cells expressing the peptide. In the manuscript, they also explained the molecular action of the peptide.
During ER stress, unfolded peptides accumulate in the ER and activate the unfolded protein response (UPR). GRP78/BiP plays a pivotal role in adjusting protein folding capacity in the UPR by triggering three stress sensors: IRE1α, ATF6 and PERK. These are transmembrane proteins at the interface of the ER and the cytoplasm that activate a cascade of events with the aim of restoring cell survival by increasing the protein folding capacity of the cell (IRE1α and ATF6), as well as reducing overall protein synthesis (PERK). However severe accumulation of aggregates/unfolded proteins turns the UPR into a pro-apoptotic pathway, leading to cell death.
Our study could show that overexpression of the Bag-1 peptide unbalanced the UPR towards its pro-apoptotic function. In fact they observed that ectopic expression of the peptide leads to downregulation of the three UPR branches as well as to an increase of UPR-related pro-apoptotic markers like the transcription factor CHOP and cleavage of PARP and Caspase-4.
The Bag-1 peptide showed a rather specific effect as it reduced growth of malignant but not benign prostate cells correlating with the cellular level of GRP78/BiP protein expression. Since GRP78/BiP is found overexpressed in many malignancies, the Bag-1 peptide may be a candidate peptide for a broad-range tumor therapy. Furthermore, the selective expression of GRP78/BiP on cancer cell surfaces offers the option of employing this peptide for diagnostic purposes.
Written by:
Danilo Maddalo and Andrew C. B. Cato as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Karlsruhe Institute of Technology, Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
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