Increased expression of the glioma-associated antigen ARF4L after loss of the tumor suppressor PTEN. Laboratory investigation.
OBJECTIVE
Despite recent advances in cancer immunotherapy, cellular mechanisms controlling expression of tumor-associated antigens are poorly understood. Mutations in cancer cells, such as loss of PTEN, may increase expression of tumor-associated antigens. The authors investigated the relationship between PTEN status and the expression of a glioma-associated antigen, adenosine diphosphate-ribosylation factor 4-like (ARF4L) protein.


METHODS
Human glioma cell lines with confirmed PTEN status were examined by Northern blot analysis and quantitative polymerase chain reaction. Western blot analysis was used to measure ARF4L protein levels across multiple cell lines.


RESULTS
The loss of PTEN was shown to lead to increased levels of ARF4L protein but no change in transcript levels. Cell lines with serial mutations, including activation of Ras and Akt pathways, also demonstrated increased levels of ARF4L protein, which decreased after treatment with rapamycin. The ARF4L transcript preferentially localized to the polysomal compartment after PTEN loss in glioma or activation of Akt in human astrocytes.


CONCLUSIONS
Expression of ARF4L is controlled by the activated Akt/mTOR pathway, which is a downstream effect of the loss of PTEN function. Mutations leading to oncogenesis may impact the regulation and expression of tumor specific antigens. Screening of mutation status in glioma may be helpful in selecting patients for immunotherapy trials in the future.
Chi
John H
JH
Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, California 94143, USA.
Panner
Amith
A
Cachola
Kristine
K
Crane
Courtney A
CA
Murray
Joseph
J
Pieper
Russell O
RO
James
C David
CD
Parsa
Andrew T
AT
D020727:ADP-Ribosylation Factors / Q000032:analysis* / Q000187:drug effects / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000032:analysis* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011132:Polyribosomes / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D014158:Transcription, Genetic / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020727:ADP-Ribosylation Factors; C116036:ARL4A protein, human; D020123:Sirolimus