Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition.
BACKGROUND
Activating transcription factor-3 (ATF3) is involved in the complex process of cellular stress response. However, its exact role in cancer is discussed controversially because both tumor suppressive and oncogenic effects have been described. Here we followed-up on our previous observation that inhibition of Hsp90 may increase ATF3 expression and sought to determine the role of ATF3 in colon cancer.


METHODS
Regulation of ATF3 was determined in cancer cells using signaling inhibitors and a heat-shock protein-90 (Hsp90) antagonist. Human HCT116 cancer cells were stably transfected with an ATF3-shRNA or a luciferase-shRNA expression plasmid and alterations in cell motility were assessed in migration assays. The impact of ATF3 down-regulation on cancer growth and metastasis were investigated in a subcutaneous tumor model, a model of hepatic tumor growth and in a model of peritoneal carcinomatosis. Human colon cancer tissues were analyzed for ATF3 expression.


RESULTS
The results show that therapeutic Hsp90 inhibition substantially up-regulates the expression of ATF3 in various cancer cells, including colon, gastric and pancreatic cancer. This effect was evident both in vitro and in vivo. RNAi mediated knock-down of ATF3 in HCT116 colon cancer cells significantly increased cancer cell migration in vitro. Moreover, in xenogenic mouse models, ATF3 knock-down promoted subcutaneous tumor growth and hepatic metastasis, as well as peritoneal carcinomatosis. Importantly, ATF3 expression was lower in human colon cancer specimens, as compared to corresponding normal surrounding tissues, suggesting that ATF3 may represent a down-regulated tumor suppressor in colon cancer.


CONCLUSIONS
In conclusion, ATF3 down-regulation in colon cancer promotes tumor growth and metastasis. Considering that blocking Hsp90 induces ATF3 expression, Hsp90 inhibition may represent a valid strategy to treat metastatic colon cancer by up-regulating this anti-metastatic transcription factor.
Department of Surgery, University of Regensburg Medical Center, Franz-Josef Strauß Allee 11, 93042 Regensburg, Germany.
Christina
C
Hackl
Sven A
SA
Lang
Christian
C
Moser
Akira
A
Mori
Stefan
S
Fichtner-Feigl
Claus
C
Hellerbrand
Wolfgang
W
Dietmeier
Hans J
HJ
Schlitt
Edward K
EK
Geissler
Oliver
O
Stoeltzing
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin