Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro

Wegert, Jenny; Bausenwein, Sabrina; Kneitz, Susanne; Roth, Sabine; Graf, Norbert; Geissinger, Eva; Gessler, Manfred

doi:10.1186/1476-4598-10-136

Cited by 22 publications

(31 citation statements)

References 24 publications

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“…The pro-apoptotic effect of fenretinide has been shown in various cancer cell lines including HeLa and breast cancer cell lines, whereas ATRA has shown no growth inhibition effect in these cell lines (26). Fenretinide also induces apoptosis/necrosis in primary Wilm’s tumor cell, but ATRA promotes cell growth (27). The apoptosis effect of fenretinide is cancer cell specific, it does not induce apoptosis in normal hepatocyte (15).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells

Ying

Liu

et al. 2013

Biochemical Pharmacology

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Fenretinide is significantly more effective in inducing apoptosis in cancer cells than all-trans retinoic acid (ATRA). The current study uses a genome-wide approach to understand the differential role fenretinide and ATRA have in inducing apoptosis in Huh7 cells. Fenretinide and ATRA-induced gene expressions and DNA bindings were profiled using microarray and chromatin immunoprecipitation with anti-RXRα antibody. The data showed that fenretinide was not a strong transcription regulator. Fenretinide only changed the expressions of 1 093 genes, approximately three times less than the number of genes regulated by ATRA (2 811). Biological function annotation demonstrated that both fenretinide and ATRA participated in pathways that determine cell fate and metabolic processes. However, fenretinide specifically induced Fas/TNFα-mediated apoptosis by increasing the expression of pro-apoptotic genes i.e., DEDD2, CASP8, CASP4, and HSPA1A/B; whereas, ATRA induced the expression of BIRC3 and TNFAIP3, which inhibit apoptosis by interacting with TRAF2. In addition, fenretinide inhibited the expression of the genes involved in RAS/RAF/ERK-mediated survival pathway. In contrast, ATRA increased the expression of SOSC2, BRAF, MEK, and ERK genes. Most genes regulated by fenretinide and ATRA were bound by RXRα, suggesting a direct effect. This study revealed that by regulating fewer genes, the effects of fenretinide become more specific and thus has fewer side effects than ATRA. The data also suggested that fenretinide induces apoptosis via death receptor effector and by inhibiting the RAS/RAF/ERK pathway. It provides insight on how retinoid efficacy can be improved and how side effects in cancer therapy can be reduced.

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Section: Discussionmentioning

confidence: 99%

Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells

Ying

Liu

et al. 2013

Biochemical Pharmacology

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“…Lapatinib-resistant cell lines (rBT474, rSKBR3, rAu565, and rSUM190) were generated and continuously maintained in 1 μ M lapatinib, as previously described [17,18]. The 4G10 anti-phosphotyrosine (p-tyr) antibody was purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Details of the methods used for SDS-PAGE and Western blot analysis have been previously described [17,18,26]. In brief, membranes were incubated with primary antibodies, washed several times in PBS, and then incubated with a fluorescence-conjugated secondary antibody at a 1:10,000 dilution with 5% try milk in PBS for 60 minutes, protected from light.…”

Section: Methodsmentioning

confidence: 99%

An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models

et al. 2013

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IntroductionThe human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase (RTK) oncogene is an attractive therapeutic target for the treatment of HER2-addicted tumors. Although lapatinib, an FDA-approved small-molecule HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), represents a significant therapeutic advancement in the treatment of HER2+ breast cancers, responses to lapatinib have not been durable. Consequently, elucidation of mechanisms of acquired therapeutic resistance to HER-directed therapies is of critical importance.MethodsUsing a functional protein-pathway activation mapping strategy, along with targeted genomic knockdowns applied to a series of isogenic-matched pairs of lapatinib-sensitive and resistant cell lines, we now report an unexpected mechanism of acquired resistance to lapatinib and similar TKIs.ResultsThe signaling analysis revealed that whereas HER2 was appropriately inhibited in lapatinib-resistant cells, EGFR tyrosine phosphorylation was incompletely inhibited. Using a targeted molecular knockdown approach to interrogate the causal molecular underpinnings of EGFR-persistent activation, we found that lapatinib-resistant cells were no longer oncogene addicted to HER2-HER3-PI3K signaling, as seen in the parental lapatinib-sensitive cell lines, but instead were dependent on a heregulin (HRG)-driven HER3-EGFR-PI3K-PDK1 signaling axis. Two FDA-approved EGFR TKIs could not overcome HRG-HER3-mediated activation of EGFR, or reverse lapatinib resistance. The ability to overcome EGFR-mediated acquired therapeutic resistance to lapatinib was demonstrated through molecular knockdown of EGFR and treatment with the irreversible pan-HER TKI neratinib, which blocked HRG-dependent phosphorylation of HER3 and EGFR, resulting in apoptosis of resistant cells. In addition, whereas HRG reversed lapatinib-mediated antitumor effects in parental HER2+ breast cancer cells, neratinib was comparatively resistant to the effects of HRG in parental cells. Finally, we showed that HRG expression is an independent negative predictor of clinical outcome in HER2+ breast cancers, providing potential clinical relevance to our findings.ConclusionsMolecular analysis of acquired therapeutic resistance to lapatinib identified a new resistance mechanism based on incomplete and "leaky" inhibition of EGFR by lapatinib. The selective pressure applied by incomplete inhibition of the EGFR drug target resulted in selection of ligand-driven feedback that sustained EGFR activation in the face of constant exposure to the drug. Inadequate target inhibition driven by a ligand-mediated autocrine feedback loop may represent a broader mechanism of therapeutic resistance to HER TKIs and suggests adopting a different strategy for selecting more effective TKIs to advance into the clinic.

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“…UAB30 has minimal toxicity compared to other retinoids [7, 9 – 11], and has recently been found to be effective in decreasing xenograft tumor growth in neuroblastoma [12]. Investigators have demonstrated the effectiveness of retinoids against adult liver [13] and kidney tumors [14]. These data in neuroblastoma [12], and the prior results with retinoids in adult renal and hepatic malignancies [13, 14], led us to believe that UAB30 may have an effect upon tumorigenicity in rare pediatric renal and hepatic malignancies.…”

Section: Introductionmentioning

confidence: 99%

“…Investigators have demonstrated the effectiveness of retinoids against adult liver [13] and kidney tumors [14]. These data in neuroblastoma [12], and the prior results with retinoids in adult renal and hepatic malignancies [13, 14], led us to believe that UAB30 may have an effect upon tumorigenicity in rare pediatric renal and hepatic malignancies.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies

Waters

Stewart

Atigadda

et al. 2016

Molecular Cancer Therapeutics

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Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side effect profile. In this current study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo. We successfully demonstrated decreased cellular proliferation, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should further be investigated as a developing therapeutic in these rare and difficult to treat, pediatric solid organ tumors.

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Retinoic acid pathway activity in wilms tumors and characterization of biological responses in vitro

Cited by 22 publications

References 24 publications

Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells

Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells

An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models

Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies

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