Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells.
BACKGROUND
The Ral guanine nucleotide-exchange factors (RalGEFs) serve as key effectors for Ras oncogene transformation of immortalized human cells. RalGEFs are activators of the highly related RalA and RalB small GTPases, although only the former has been found to promote Ras-mediated growth transformation of human cells. In the present study, we determined whether RalA and RalB also had divergent roles in promoting the aberrant growth of pancreatic cancers, which are characterized by the highest occurrence of Ras mutations.


RESULTS
We now show that inhibition of RalA but not RalB expression universally reduced the transformed and tumorigenic growth in a panel of ten genetically diverse human pancreatic cancer cell lines. Despite the apparent unimportant role of RalB in tumorigenic growth, it was nevertheless critical for invasion in seven of nine pancreatic cancer cell lines and for metastasis as assessed by tail-vein injection of three different tumorigenic cell lines tested. Moreover, both RalA and RalB were more commonly activated in pancreatic tumor tissue than other Ras effector pathways.


CONCLUSIONS
RalA function is critical to tumor initiation, whereas RalB function is more important for tumor metastasis in the tested cell lines and thus argues for critical, but distinct, roles of Ral proteins during the dynamic progression of Ras-driven pancreatic cancers.
Lim
Kian-Huat
KH
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
O'Hayer
Kevin
K
Adam
Stacey J
SJ
Kendall
S Disean
SD
Campbell
Paul M
PM
Der
Channing J
CJ
Counter
Christopher M
CM
D000230:Adenocarcinoma / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D014183:Transplantation, Heterologous; D020725:ral GTP-Binding Proteins / Q000502:physiology*
C483163:Ralb protein, human; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins