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 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.
Weidle
Ulrich H
UH
Roche Diagnostics GmbH, Pharma Research, D-82377 Penzberg, Germany. ulrich.weidle@roche.com
Evtimova
Vesna
V
Alberti
Saverio
S
Guerra
Emanuela
E
Fersis
Nikos
N
Kaul
Sepp
S
D000230:Adenocarcinoma / Q000378:metabolism / Q000556:secondary; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001215:Asparaginase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D003536:Cystadenocarcinoma / Q000378:metabolism / Q000556:secondary; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D034741:RNA, Small Interfering; C466840:ASRGL1 protein, human; D001215:Asparaginase