The Arf-like GTPase Arl8b is essential for three-dimensional invasive growth of prostate cancer in vitro and xenograft formation and growth in vivo.
Cancer is a multistep process that requires cells to respond appropriately to the tumor microenvironment, both in early proliferative stages and in later invasive disease. Arl8b is a lysosome localized Arf-like GTPase that controls the spatial distribution of lysosomes via recruitment of kinesin motors. Common features of the tumor microenvironment such as acidic extracellular pH and various growth factors stimulate lysosome trafficking to the cell periphery (anterograde), which is critical for tumor invasion by facilitating the release of lysosomal proteases to promote matrix remodeling. Herein we report for the first time that Arl8b regulates anterograde lysosome trafficking in response to hepatocyte growth factor, epidermal growth factor, and acidic extracellular pH. Depletion of Arl8b results in juxtanuclear lysosome aggregation, and this effect corresponds with both diminished invasive growth and proteolytic extracellular matrix degradation in a three-dimensional model of prostate cancer. Strikingly, we found that depletion of Arl8b abolishes the ability of prostate cancer cells to establish subcutaneous xenografts in mice. We present evidence that Arl8b facilitates lipid hydrolysis to maintain efficient metabolism for a proliferative capacity in low nutrient environments, suggesting a likely explanation for the complete inability of Arl8b-depleted tumor cells to grow in vivo. In conclusion, we have identified two mechanisms by which Arl8b regulates cancer progression: 1) through lysosome positioning and protease release leading to an invasive phenotype and 2) through control of lipid metabolism to support cellular proliferation. These novel roles highlight that Arl8b is a potential target for the development of novel anti-cancer therapeutics.
Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.
Samantha S
SS
Dykes
Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.
Alana L
AL
Gray
Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.
David T
DT
Coleman
Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.|Department of Molecular and Cellular Physiology, LSU Health Shreveport, Shreveport, LA, USA.|Current address: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA, USA.
Madhurima
M
Saxena
Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA.
Charles A
CA
Stephens
Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.
Jennifer L
JL
Carroll
Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.|Department of Molecular and Cellular Physiology, LSU Health Shreveport, Shreveport, LA, USA.|Current address: Texas Tech University Health Sciences Center, Lubbock, TX, USA.
Kevin
K
Pruitt
Department of Microbiology and Immunology, LSU Health Shreveport, Shreveport, LA, USA.|Feist-Weiller Cancer Center, LSU Health Shreveport, Shreveport, LA, USA.
James A
JA
Cardelli
D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction
C511801:ARL8B protein, human; D020727:ADP-Ribosylation Factors
Arl8b; invasion; lipid metabolism; lysosome; xenograft