KRAS-Independent Macropinocytosis in Pancreatic Cancer.

G Aaron Hobbs, Channing J Der

Journal: Sub-cellular biochemistry 2022;98():205-221

PMID: 35378710

Abstract

Macropinocytosis is a critical route of nutrient acquisition in pancreatic cancer cells. Constitutive macropinocytosis is promoted by mutant KRAS, which activates the PI3Kα lipid kinase and RAC1, to drive membrane ruffling, macropinosome uptake and processing. However, our recent study on the KRAS mutant indicated the presence of a KRAS-independent mode of macropinocytosis in pancreatic cancer cell lines, thereby increasing the complexity of this process. We found that KRAS-mutant cell lines promote macropinocytosis independent of KRAS activity using PI3Kγ and RAC1, highlighting the convergence of regulation on RAC signaling. While macropinocytosis has been proposed to be a therapeutic target for the treatment of pancreatic cancer, our studies have underscored how little we understand about the activation and regulation of this metabolic process. Therefore, this review seeks to highlight the differences in macropinocytosis regulation in the two cellular subtypes while also highlighting the features that make the KRAS mutant atypical.

Address: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA. [email protected].; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA. [email protected].; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

DOI: 10.1007/978-3-030-94004-1_11