Increased expression of the glioma-associated antigen ARF4L after loss of the tumor suppressor PTEN

Laboratory investigation

John H. Chi M.D., M.P.H., Amith Panner Ph.D., Kristine Cachola B.A., Courtney A. Crane Ph.D., Joseph Murray B.S., Russell O. Pieper Ph.D., C. David James Ph.D. and Andrew T. Parsa M.D., Ph.D.
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  • Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, California
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Object

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.

Abbreviations used in this paper:ARF4L = adenosine diphosphate–ribosylation factor 4–like; EDTA = ethylenediaminetetraacetic acid; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; GBM = glioblastoma multiforme; hTERT = human telomerase reverse transcriptase; mTOR = mammalian target of rapamycin; NHA = normal human astrocyte; PCR = polymerase chain reaction; PI3-K = phosphatidylinositol 3-kinase; PTEN = phosphatase and tensin homolog; TAA = tumor-associated antigen; UCSF = University of California, San Francisco; 4-HT = 4-hydroxytamoxifen.

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Contributor Notes

Address correspondence to: Andrew T. Parsa, M.D., Ph.D., 505 Parnassus Avenue, M779, Box 0112, San Francisco, California 94143. email: parsaa@neurosurg.ucsf.edu.
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