Inhibition of RAS-mediated transformation and tumorigenesis by targeting the downstream E3 ubiquitin ligase seven in absentia homologue.
Constitutively active RAS small GTPases promote the genesis of human cancers. An important goal in cancer biology is to identify means of countervailing activated RAS signaling to reverse malignant transformation. Oncogenic K-RAS mutations are found in virtually all pancreatic adenocarcinomas, making the RAS pathway an ideal target for therapeutic intervention. How to best contravene hyperactivated RAS signaling has remained elusive in human pancreatic cancers. Guided by the Drosophila studies, we reasoned that a downstream mediator of RAS signals might be a suitable anti-RAS target. The E3 ubiquitin ligase seven in absentia (SINA) is an essential downstream component of the Drosophila RAS signal transduction pathway. Thus, we determined the roles of the conserved human homologues of SINA, SIAHs, in mammalian RAS signaling and RAS-mediated tumorigenesis. We report that similar to its Drosophila counterpart, human SIAH is also required for oncogenic RAS signaling in pancreatic cancer. Inhibiting SIAH-dependent proteolysis blocked RAS-mediated focus formation in fibroblasts and abolished the tumor growth of human pancreatic cancer cells in soft agar as well as in athymic nude mice. Given the high level of conservation of RAS and SIAH function, our study provides useful insights into altered proteolysis in the RAS pathway in tumor initiation, progression, and oncogenesis. By targeting SIAH, we have found a novel means to contravene oncogenic RAS signaling and block RAS-mediated transformation/tumorigenesis. Thus, SIAH may offer a novel therapeutic target to halt tumor growth and ameliorate RAS-mediated pancreatic cancer.
Schmidt
Rebecca L
RL
Department of Biochemistry and Molecular Biology, Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Park
Cheol Hong
CH
Ahmed
Atique U
AU
Gundelach
Justin H
JH
Reed
Nanette R
NR
Cheng
Shen
S
Knudsen
Bruce E
BE
Tang
Amy H
AH
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D017931:DNA Primers; D005347:Fibroblasts / Q000502:physiology; D011905:Genes, ras; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D010179:Pancreas; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000098563:Seven in Absentia Proteins
D017931:DNA Primers; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins