Identification of differentially expressed genes associated with androgen‐independent growth of prostate cancer

Mohler, James L.; Morris, Tammy L.; Ford, O. Harris; Alvey, Rudolf F.; Sakamoto, Choitsu; Gregory, Christopher

doi:10.1002/pros.10086

Cited by 56 publications

(48 citation statements)

References 25 publications

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“…Other investigators have reported similar findings (11)(12)(13). Glynne-Jones et al (11) analyzed 85 clinical samples by Taqman analysis and showed that tomoregulin mRNA is significantly overexpressed in prostate carcinomas when compared with their benign counterpart.…”

Section: Discussionsupporting

confidence: 82%

Targeting Tomoregulin for Radioimmunotherapy of Prostate Cancer

Zhao¹,

Schneider²,

Biroc³

et al. 2005

Cancer Research

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Radiotherapy is an effective approach for the treatment of local prostate cancer. However, once prostate cancer metastasizes, radiotherapy cannot be used due to the distribution of multiple metastases to lymph nodes and bones. In contrast, radioimmunotherapy should still be efficacious in metastatic prostate cancer as radioisotopes are brought to tumor cells by targeting antibodies. Here we identify and validate a prostate-expressed molecule, tomoregulin, as a target for radioimmunotherapy of prostate cancer. Tomoregulin is a transmembrane protein selectively expressed in the brain, prostate, and prostate cancer, but not expressed in other normal tissues. Immunohistochemical studies of tomoregulin protein in clinical samples show its location in the luminal epithelium of normal prostate, benign prostatic hyperplasia, and prostatic intraepithelial neoplasia. More importantly, the tomoregulin protein is expressed in primary prostate tumors and in their lymph node and bone metastases. The nature of tomoregulin as a transmembrane protein and its tissue-specific expression make tomoregulin an attractive target for radioimmunotherapy, in which tomoregulin-specific antibodies will deliver a radioisotope to prostate tumor cells and metastases. Indeed, biodistribution studies using a prostate tumor xenograft model showed that the 111 In-labeled antitomoregulin antibody 2H8 specifically recognizes tomoregulin protein in vivo, leading to a strong tumor-specific accumulation of the antibody. In efficacy studies, a single i.p. dose of 150 MCi (163 Mg) 90 Y-labeled 2H8 substantially inhibits the growth rate of established LNCaP human prostate tumor xenograft in nude mice but produces no overt toxicity despite crossreactivity of 2H8 with mouse tomoregulin. Our data clearly validate tomoregulin as a target for radioimmunotherapy of prostate cancer. (Cancer Res 2005; 65(7): 2846-53)

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Section: Discussionsupporting

confidence: 82%

Targeting Tomoregulin for Radioimmunotherapy of Prostate Cancer

Zhao¹,

Schneider²,

Biroc³

et al. 2005

Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although several signaling pathways are involved in the regulation of PSA gene expression (26,27), the presence of PSA in recurrent prostate cancer is consistent with the presence of an activated androgen receptor. In addition, PSA, as well as other androgen-regulated genes, were expressed before and after castration in tumor models of androgen-dependent prostate cancer as shown by differential expression (26), subtractive hybridization (28), and cDNA microarray (29).…”

Section: Discussionmentioning

confidence: 99%

The Androgen Axis in Recurrent Prostate Cancer

Mohler

Gregory

Ford

et al. 2004

Clinical Cancer Research

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612

463

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Purpose. Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence.Experimental Design. Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay.Results. Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 ؎ SD 0.115 and percentage positive nuclei, 83.7 ؎ 11.6) was similar to benign prostate (mean optical density, 0.315 ؎ 0.044 and percentage positive nuclei, 77.3 ؎ 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 ؎ 2.34 pmol/g tissue) and benign prostate (3.26 ؎ 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P ‫؍‬ 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgenregulated gene product, prostate-specific antigen, at 8.80 ؎ 10.80 nmol/g tissue.Conclusions. Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.

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“…18 eEF1A1, which maps to 6q14, is amplified in some childhood brain tumors, and eEF1A1 is over-expressed in pancreas, breast, lung, and colon tumors. [29][30][31] In prostate carcinoma, the dominant prostate tumor-inducing gene 1 (PTI-1), with a 97.7% DNA sequence homology to eEF1A1, was identified by PCR. 30 Its expression occurs in breast, colon, and lung cancer cells, but not in normal cells, and it can transform rodent fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

Kim

Namkung

Yoon

et al. 2009

Laboratory Investigation

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The formation of a pH gradient, which is characterized by intracellular alkalinization and extracellular acidification, plays a key role in the growth and metastasis of tumor cells. However, the underlying mechanisms of alkalinization-induced cell growth are not known. In this study, we investigated the roles of eukaryotic translation elongation factor 1 a (eEF1A) in alkalinization-induced cell growth. In all cell lines tested (NIH3T3, HEK293, and HeLa), cell growth was affected by the modulation of intracellular pH. In general, weak intracellular alkalinization produced increased cell growth, whereas intracellular acidification resulted in decreased cell growth. It is interesting to note that portions of actin-bound eEF1A proteins were gradually reduced from acidic to alkaline conditions, suggesting an increase in levels of functionally active, free-form eEF1A. Over-expression of eEF1A caused increased cell growth in HeLa cells. It should be noted that dissociation of eEF1A from actin by transfection with the actin-binding domain deleted eEF1A construct further increased cell growth under acidic conditions, whereas most of the intact eEF1A was bound to actin. Conversely, knockdown of eEF1A by treatment with eEF1A1 and eEF1A2 siRNAs nullified the effects of alkalinization-induced cell growth. The above findings suggest that an increase in free-form eEF1A under alkaline conditions plays a critical role in alkalinization-induced cell growth.

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Identification of differentially expressed genes associated with androgen‐independent growth of prostate cancer

Abstract: One or more of these genes may represent an appropriate target to prevent, delay or treat recurrent prostate cancer.

Cited by 56 publications

References 25 publications

Targeting Tomoregulin for Radioimmunotherapy of Prostate Cancer

Targeting Tomoregulin for Radioimmunotherapy of Prostate Cancer

The Androgen Axis in Recurrent Prostate Cancer

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

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