Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion.
Akikazu HaradaShinji MatsumotoYoshiaki YasumizuKensaku ShojimaToshiyuki AkamaHidetoshi EguchiAkira KikuchiPublished in: eLife (2021)
Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF-RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C-IQGAP1-MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.
Keyphrases
- wild type
- extracellular matrix
- cell migration
- stem cells
- poor prognosis
- squamous cell carcinoma
- type diabetes
- dendritic cells
- cell proliferation
- young adults
- cardiovascular events
- regulatory t cells
- insulin resistance
- metabolic syndrome
- binding protein
- immune response
- oxidative stress
- adipose tissue
- small molecule
- high fat diet induced
- type iii
- diabetic rats
- amino acid
- endothelial cells
- protein kinase
- squamous cell