Cell Growth Stimulation by CRASH, an Asparaginase-like Protein Overexpressed in Human Tumors and Metastatic Breast Cancers

The gene encoding CRASH, a human asparaginase-like protein, has been cloned and its transcriptional activation has been detected in gynecologic cancers. To define the expression of CRASH in human tumors and its possible functional role, monoclonal antibodies against the CRASH protein have been gener...

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Bibliographic Details
Published in:Anticancer research 2009-04, Vol.29 (4), p.951-963
Main Authors: WEIDLE, Ulrich H, EVTIMOVA, Vesna, ALBERTI, Saverio, GUERRA, Emanuela, FERSIS, Nikos, KAUL, Sepp
Format: Article
Language:English
Subjects:
Adenocarcinoma - metabolism
Adenocarcinoma - secondary
Amino Acid Sequence
Animals
Antibodies, Monoclonal - immunology
Asparaginase - antagonists & inhibitors
Asparaginase - genetics
Asparaginase - metabolism
Autoantigens - genetics
Autoantigens - metabolism
Biological and medical sciences
Blotting, Western
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Carcinoma, Transitional Cell - metabolism
Carcinoma, Transitional Cell - secondary
Cell Line, Tumor
Cystadenocarcinoma - metabolism
Cystadenocarcinoma - secondary
Female
Gynecology. Andrology. Obstetrics
Humans
Immunoenzyme Techniques
Mammary gland diseases
Medical sciences
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Prognosis
RNA, Small Interfering - pharmacology
Sequence Homology, Amino Acid
Tumors
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Summary:The gene encoding CRASH, a human asparaginase-like protein, has been cloned and its transcriptional activation has been detected in gynecologic cancers. To define the expression of CRASH in human tumors and its possible functional role, monoclonal antibodies against the CRASH protein have been generated. In non-transformed tissues CRASH was only detected in testis, brain, esophagus, prostate and proliferating endometrium. On the other hand, 36/50 ovarian carcinomas, 16/78 mammary carcinomas, 6/6 uroepithelial bladder carcinomas and 5/33 colon carcinomas scored positive for CRASH, with the absence of reactivity in the corresponding normal tissues. Strikingly, 11 out of the 16 breast cancers that expressed CRASH were metastatic, nominating CRASH to be functionally relevant in tumor progression. Twenty-eight out of 42 endometrium tumors expressed CRASH at high levels as did 5/41 prostate carcinomas, as well as ovary and breast cancers, indicating a regulation of CRASH expression by sex hormones. A bona fide estrogen responsive element was detected at bases -201/-183. This proved to be highly preserved across species, supporting an actual functional role. Asparaginase-like proteins play a role in growth regulation and signaling by p70 S6 kinase. The somatic knock-out of CRASH resulted in significant inhibition of growth of KM12L4A colon carcinoma cells, which abundantly express CRASH, whereas the proliferation of the syngeneic, weakly-expressing, slowly-growing KL12SM was not affected. These results are consistent with a selective growth advantage for aggressive cancers expressing CRASH, and nominate CRASH as a novel diagnostic and therapeutic tumor target.
ISSN:0250-7005
1791-7530