Naslov
Gli3 and GSK3β play a major role in colon cancer

Autori
Car, Diana ; Sabol, Maja ; Gojević, Ante ; Martinić, Martina ; Ozretić, Petar ; Musani, Vesna ; Levanat, Sonja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Periodicum Biologorum, Suppl 1 / Levanat, Sonja ; Levačić Cvok, Mirela ; Musani, Vesna ; Car, Diana ; Osmak, Maja ; Herak Bosnar, Maja ; Slade, Neda ; Stojanović, Nikolina - Zagreb : Hrvatsko prirodoslovno društvo, 2012, 44-44

Skup
HDIR-2 „From Bench to Clinic“, Second Meeting with International Participation of the Croatian association for Cancer Research

Mjesto i datum
Zagreb, Hrvatska, 08.11.2012. - 09.11.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
Hedgehog signaling; Gli3; GSK3beta

Sažetak
The Hedgehog-Gli (Hh-Gli) signaling pathway is a developmental pathway, which is often found aberrantly active in various tumors. After binding of the ligand Hedgehog to its transmembrane receptor Patched (Ptch), Smoothened (Smo) is translocated to the cell membrane where it starts a signaling cascade, ultimately leading to the translocation of the Gli transcription factors to the nucleus. Gli1 is an activator of the pathway, while Gli2 and Gli3 can act as activators or repressors, depending on the cellular context. Gli proteins are negatively regulated by the Suppressor of Fused (SuFu), which binds Gli proteins and prevents their translocation to the nucleus, and by three kinases (PKA, GSK3β and CK1) which tag the Gli proteins for degradation or processing into repressor forms. GSK3β is a multifunctional Ser/Thr kinase involved in a series of signaling pathways and mainly has a tumor suppressor activity. In contrast to this activity, its overexpression and pro-survival role has been found in several human cancer cells, such as ovarian, colon, pancreatic cancer cells. Our aim was to investigate the role of Hh signaling in colon cancer. We found high expression of Gli3 and GSK3β in colon cancer tissue samples which showed positive correlation with DUKES’ stage. The SW-480 cell was used to investigate the role of these two proteins more closely. This cell line has an active Hh signaling pathway and also shows high expression of GSK3β and Gli3 with a higher proportion of the Gli3 activator form. We confirmed that the overexpressed GSK3β is essential for the survival of SW-480 cells, since its inhibition with lithium chloride (a known inhibitor of GSK3β) leads to decreased cell viability. Also, GSK3β inhibition has a remarkable effect on Gli3 protein, leading to its processing into the Gli3 repressor form. As a consequence the Hh signaling pathway is downregulated. We propose that in colon cancer cells GSK3β is aberrantly activated and cannot exert its proper function in regulating Gli3 processing into its repressor form. This keeps the Hh signaling active and promotes cell survival. Therefore, GSK3β may prove to be an interesting therapeutic target for treatment of colon cancer and other types of cancer with aberrant activaton of GSK3β and Gli3.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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