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The Hedgehog-Gli signaling in tumors and implications for therapy


Levanat, Sonja; Car, Diana; Sabol, Maja; Musani, Vesna; Ozretic, Petar; Gojević, Ante; Oresković, Slavko
The Hedgehog-Gli signaling in tumors and implications for therapy // FEBS 3+ Meeting, From molecules to life and back / Dumic, Jerka ; Kovarik, Zrinka ; Varljen, Jadranka (ur.).
zagreb, Hrvatska: Croatian Society of Biochemistry and Molecular Biology, 2012. str. 74-74 (pozvano predavanje, međunarodna recenzija, sažetak, znanstveni)


Naslov
The Hedgehog-Gli signaling in tumors and implications for therapy

Autori
Levanat, Sonja ; Car, Diana ; Sabol, Maja ; Musani, Vesna ; Ozretic, Petar ; Gojević, Ante ; Oresković, Slavko

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

Izvornik
FEBS 3+ Meeting, From molecules to life and back / Dumic, Jerka ; Kovarik, Zrinka ; Varljen, Jadranka - Zagreb, Hrvatska : Croatian Society of Biochemistry and Molecular Biology, 2012, 74-74

ISBN
978-953-95551-4-4

Skup
FEBS 3+ Meeting, From molecules to life and back

Mjesto i datum
Opatija, Hrvatska, 13-16.6.2012

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Signaling; Hedgehog-Gli; SHH; therapy

Sažetak
The Hedgehog-Gli (Hh-Gli) signaling pathway is a developmental pathway, which is often found aberrantly active in various tumors. The pathway is a highly coordinated and orchestrated network involving binding of the ligand Hedgehog (Hh) to its receptor, a twelve transmembrane protein, Patched (Ptch). This causes Ptch to release its repression over the coreceptor Smoothened (Smo), a seven transmembrane protein and triggers a cascade of events in the cytoplasm leading to activation of the transcription factor Gli and transcription of target genes. The Gli proteins are regulated by the Suppressor of Fused (SuFu), Protein Kinase A (PKA), Glycogen Synthase Kinase 3β (GSK3β) and Casein Kinase 1 (CK1). The involvement of the Hh-Gli signaling pathway in a variety of human cancers is still not completely elucidated but, preclinical in vitro and in vivo data demonstrate a role of this pathway in cancer pathogenesis, self-renewal and chemotherapy resistance. Our results on several different human cancers show different levels of pathway alterations. We found that the increased level of GSK3b is essential for survival of colon cancer cells and this alters Gli3 processing, keeping the Hh-Gli signaling pathway active. After GSK3 inhibition, Gli3 is processed into its repressor form, the Hh-Gli signaling pathway is downregulated and the proliferation of colon cancer cells is decreased. This suggests a major role for the interplay of GSK3 and Gli3 in the regulation of this pathway in colon cancer. On the other hand, in ovarian tumor pathogenesis we found a difference in SHH gene expression between borderline tumors and carcinoma, with significantly higher expression in borderline tumors compared to carcinoma. However, the upregulation of Hh-Gli signaling in almost all tested samples suggests that this is an early event in ovarian tumorigenesis regardless of tumor type. Our results support the involvment of the Hh-Gli signaling pathway in the pathogenesis of tumors. To date several Smo inhibitors have been proposed as potential candidates for cancer therapy either as a single agent or in combination regimens with conventional chemotherapy. Our results confirm the importance of investigating the role of the Hh-Gli signaling pathway in cancer and they emphasize the need for a better understanding of the modes of Hh-Gli pathway regulation in different tumors, its role in tumor response to traditional therapy, as well as the interactions of the Hh-Gli pathway with other signaling pathways in order to develop better therapies based on combinations with inhibitors of the Hh-Gli signaling pathway.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti



POVEZANOST RADA


Projekt / tema
098-0982464-2461 - Prijenos signala u tumorima: Hh-Gli put, interakcije i potencijalne terapije (Sonja Levanat, )

Ustanove
Institut "Ruđer Bošković", Zagreb