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Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome.

Denard B, Pavia-Jimenez A, Chen W, Williams NS, Naina H, Collins R, Brugarolas J, Ye J - PLoS ONE (2015)

Bottom Line: Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation.Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis).From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States of America.

ABSTRACT

Background: Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin.

Methods: Mice transplanted with 6 lines of renal cell carcinoma (RCC) were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin.

Results: Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis). From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC.

Conclusion: Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1.

No MeSH data available.


Related in: MedlinePlus

CREB3L1 expression in RCC and DLBCL.(A-D) Representative IHC images of sections of the indicated tumors stained negatively or positively with anti-CREB3L1. Scale bar: 100 μm. (E) Percentage of indicated tumors stained positively with anti-CREB3L1.
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pone.0129233.g006: CREB3L1 expression in RCC and DLBCL.(A-D) Representative IHC images of sections of the indicated tumors stained negatively or positively with anti-CREB3L1. Scale bar: 100 μm. (E) Percentage of indicated tumors stained positively with anti-CREB3L1.

Mentions: The results in Fig 3A show that the percentage of RCC tumors that express CREB3L1 is quite low. This observation may explain why doxorubicin is not approved to treat RCC. On the other hand, doxorubicin is used as the primary chemotherapeutic reagent to treat DLBCL [12]. According to our hypothesis, a substantial fraction of DLBCL should express CREB3L1. To test this hypothesis, we used IHC to measure CREB3L1 expression in biopsies from 29 RCC and 14 DLBLC patients. Examples of the positive and negative staining results for each tumor were shown in Fig 6A–6D. Among the primary RCC, 19% were stained positively with anti-CREB3L1 (Fig 6E). In contrast, 70% of DLBLC showed positive staining (Fig 6E).


Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome.

Denard B, Pavia-Jimenez A, Chen W, Williams NS, Naina H, Collins R, Brugarolas J, Ye J - PLoS ONE (2015)

CREB3L1 expression in RCC and DLBCL.(A-D) Representative IHC images of sections of the indicated tumors stained negatively or positively with anti-CREB3L1. Scale bar: 100 μm. (E) Percentage of indicated tumors stained positively with anti-CREB3L1.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4482141&req=5

pone.0129233.g006: CREB3L1 expression in RCC and DLBCL.(A-D) Representative IHC images of sections of the indicated tumors stained negatively or positively with anti-CREB3L1. Scale bar: 100 μm. (E) Percentage of indicated tumors stained positively with anti-CREB3L1.
Mentions: The results in Fig 3A show that the percentage of RCC tumors that express CREB3L1 is quite low. This observation may explain why doxorubicin is not approved to treat RCC. On the other hand, doxorubicin is used as the primary chemotherapeutic reagent to treat DLBCL [12]. According to our hypothesis, a substantial fraction of DLBCL should express CREB3L1. To test this hypothesis, we used IHC to measure CREB3L1 expression in biopsies from 29 RCC and 14 DLBLC patients. Examples of the positive and negative staining results for each tumor were shown in Fig 6A–6D. Among the primary RCC, 19% were stained positively with anti-CREB3L1 (Fig 6E). In contrast, 70% of DLBLC showed positive staining (Fig 6E).

Bottom Line: Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation.Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis).From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States of America.

ABSTRACT

Background: Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin.

Methods: Mice transplanted with 6 lines of renal cell carcinoma (RCC) were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin.

Results: Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis). From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC.

Conclusion: Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1.

No MeSH data available.


Related in: MedlinePlus