Galiellalactone Is a Direct Inhibitor of the Transcription Factor STAT3 in Prostate Cancer Cells

Don‐Doncow, Nicholas; Escobar, Zilma; Johansson, Martin; Kjellström, Sven; García, Victor; Muñóz, Eduardo; Sterner, Olov; Bjartell, Anders; Hellsten, Rebecka

doi:10.1074/jbc.m114.564252

Cited by 82 publications

(81 citation statements)

References 34 publications

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“…This finding suggests that the effect of enzalutamide on SOCS3 is mediated via STAT3. We confirmed this hypothesis by blocking the transcriptional activity of STAT3 with the specific inhibitor galiellalactone (40). Inhibition of STAT3 signaling was able to completely inhibit the effect of enzalutamide on SOCS3 expression (Fig.…”

Section: Socs3 Is Expressed In Androgen Receptor-positive Prostate Casupporting

confidence: 66%

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment.Implications: SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines.

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Section: Socs3 Is Expressed In Androgen Receptor-positive Prostate Casupporting

confidence: 66%

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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“…In general, STAT3 compounds have included peptidomimetics, (31, 32) oligonucleotides (33–35), metal complexes (36, 37), and small molecule inhibitors (38–43). Inhibitors operating via DNA binding domain blockade include inS3-54 (44) as well as Galeillalactone (45). Our efforts have focused on developing small molecule inhibitors of the SH2 domain: BP-1-102 (46, 47), BP-5-87 (48), and SH-4-54 (49).…”

Section: Introductionmentioning

confidence: 99%

Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics

Arpin

Mac

Jiang

et al. 2016

Molecular Cancer Therapeutics

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Constitutively activated Signal Transducer and Activator of Transcription 3 (STAT3) protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low μM range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nM by SPR, showed no effect in a kinome screen (> 100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized 3-Dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAFs). In this co-culture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D co-cultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells.

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“…In 2001, its absolute configuration was established through a total synthesis from ( R )‐(+)‐pulegone . Galiellalactone has been found to interfere with the Stat3 signaling pathway and, because the constitutively activated Stat3 has been correlated with the malignant potential of prostate cancer, this natural product was evaluated against prostate cell cultures and in a mouse prostate cancer model (Table ) . Galiellalactone significantly suppressed DU145 and PC‐3 xenograft growth in vivo and reduced the relative mRNA expression of Bcl‐xL and Mcl‐1.…”

Section: Fungal Metabolites and Their Synthetic Analogues Evaluated Imentioning

confidence: 99%

Toward a Cancer Drug of Fungal Origin

Kornienko

Evidente²,

Vurro

et al. 2015

Medicinal Research Reviews

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Although fungi produce highly structurally diverse metabolites, many of which have served as excellent sources of pharmaceuticals, no fungi-derived agent has been approved as a cancer drug so far. This is despite a tremendous amount of research being aimed at the identification of fungal metabolites with promising anticancer activities. This review discusses the results of clinical testing of fungal metabolites and their synthetic derivatives, with the goal to evaluate how far we are from an approved cancer drug of fungal origin. Also, because in vivo studies in animal models are predictive of the efficacy and toxicity of a given compound in a clinical situation, literature describing animal cancer testing of compounds of fungal origin is reviewed as well. Agents showing the potential to advance to clinical trials are also identified. Finally, the technological challenges involved in the exploitation of fungal biodiversity and procurement of sufficient quantities of clinical candidates are discussed and potential solutions that could be pursued by researchers are highlighted.

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Galiellalactone Is a Direct Inhibitor of the Transcription Factor STAT3 in Prostate Cancer Cells

Cited by 82 publications

References 34 publications

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics

Toward a Cancer Drug of Fungal Origin

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