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The discovery, titled "Prostate specific membrane antigen associates withanaphase promoting complex and induces chromosomal instability," is outlinedin the July issue of Molecular Cancer Therapeutics, an American Associationfor Cancer Research journal and provides new insights into therapeutic benefitfor patients with advanced prostate cancer.
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The research was conducted by Dr. Ayyappan K. Rajasekaran, the Director ofNCCCR, and his research team while they were at the University of California,Los Angeles, and at NCCCR. The abundance of PSMA in prostate cancer cellsincreases as the cancer progresses into a metastatic and hormone-independentadvanced disease. Dr. Rajasekaran said, "We strongly suspected that PSMA hasa potential role in the progression of prostate cancer into an aggressivedisease. But how it participates in disease progression was not clear. Now inthis study, we identified that PSMA does have an important causative role inprostate cancer progression."
This study was initiated when the researchers found that PSMA was presentat the poles of the dividing cells. These poles are complex structures at theopposite ends of the cells that control the separation of chromosomes equallyinto daughter cells during cell division. "Presence of PSMA at the polesindicated it might have a role in cell division and chromosome segregation,and we continued our quest to understand this potential function of PSMA,"said Dr. Rajasekaran.
Human cells have 46 chromosomes. The chromosomes are vehicles that carrythe genetic material DNA from generation to generation. These chromosomes areequally divided into daughter cells during cell division. Cells have severalcheckpoints to ensure that the chromosomes are equally separated during celldivision. Anaphase-promoting complex (APC) is one such checkpoint regulatoryprotein involved in the proper segregation of chromosomes during celldivision. This complex monitors the timing of cell division and providessufficient time for cells to segregate chromosomes equally into daughtercells. Often, cancer cells have more than 46 chromosomes, a condition known asaneuploidy, which is a constant feature of aggressive, advanced, anddrug-resistant solid tumors, including prostate cancer.
Rajasekaran and his research team found that PSMA-expressing cells spentless time dividing. They found that PSMA interferes with the function of APCand induces aneuploidy in cancer cells. "When PSMA is present, cells hurriedto complete their division prior to having all their chromosomes properlysegregated," said Dr. Sigrid A. Rajasekaran, the first author of the study andthe head of the Cancer Cell Metabolism Laboratory at NCCCR.
PSMA is present in prostate cancer cells but not in normal cells.Therefore, it is an excellent therapeutic target for prostate cancer. Thereare several ongoing clinical trials for PSMA-based therapeutic interventions."Since PSMA expression is higher in metastatic compared to benign cancercells, anti-PSMA-based therapeutic strategies should target metastaticprostate cancer cells, which will benefit patients with advanced prostatecancer," the study states.
Dr. A. Rajasekaran and his team conducted their research on cell lines andare in the process of translating
