Compensating for a Missing Prostate Cancer Tumor Suppressor Gene

Cancer researchers have found that inactivation of the GRP78 gene prevented development of prostate cancer from mutated mouse epithelial tissues that normally would be prime tumor breeding grounds due to the lack of the PTEN tumor suppressor gene.

PTEN is one of the most commonly lost tumor suppressors in human cancer. During tumor development, mutations and deletions of PTEN occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell death. Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer, prostate cancer, and reduced expression is found in many other tumor types such as lung and breast cancer.

Previous studies had shown that the glucose-regulated protein GRP78 was a crucial entity in the development of prostate cancer by promoting cancer cell proliferation, mediating oncogenic signaling, and protecting cancer cells against cell death resulting from the stress of tumor development. These findings prompted investigators at the University of Southern California (Los Angeles, CA, USA) to genetically engineer a line of mice that lacked both the GRP78 and PTEN genes.

They reported in the November 25, 2008, online edition of the Proceedings of the [U.S.] National Academy of Sciences (PNAS) that mouse prostates with double conditional knockout of GRP78 and PTEN exhibited normal histology and cytology, in contrast to the invasive adenocarcinoma in mouse prostates with PTEN inactivation but with active GRP78. The lack of GRP78 prevented activation of the AKT oncogene, which would have been expected due to occur with no PTEN activity to prevent it.

"To our knowledge, this is the first demonstration that inactivation of a specific molecular chaperone from the mouse prostate epithelial cells can potently block prostate cancer development and suppress the activation of AKT, which is a protein kinase that promotes cell proliferation and survival and is a major factor in many types of cancer,” explained senior author Dr. Amy Lee, professor of biochemistry and molecular biology at the University of Southern California. "With the recent advances in identifying agents that suppress GRP78 expression, anti-GRP78 therapy may open up an entirely new approach to stop human cancer.”

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