Faculty Opinions recommendation of Inhibitors of SCF-Skp2/Cks1 E3 ligase block estrogen-induced growth stimulation and degradation of nuclear p27kip1: therapeutic potential for endometrial cancer.

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

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P172 Preclinical evidences of the therapeutic potential of ABTL0812 in endometrial cancer

10.1136/ijgc-2019-esgo.232 ◽

2019 ◽

Author(s):

A Gil-Moreno ◽

I Felip ◽

CP Moiola ◽

C Megino-Luque ◽

C Lopez-Gil ◽

...

Keyword(s):

Endometrial Cancer ◽

Therapeutic Potential

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Identification of a Cereblon-Independent Protein Degradation Pathway in Residual Myeloma Cells Treated with Immunomodulatory Drugs

Blood ◽

10.1182/blood.v126.23.913.913 ◽

2015 ◽

Vol 126 (23) ◽

pp. 913-913 ◽

Cited By ~ 2

Author(s):

Rakesh Verma ◽

Zifeng Mai ◽

Mina Xu ◽

Lin Zhang ◽

Kavita Dhodapkar ◽

...

Keyword(s):

Conflicts Of Interest ◽

Residual Disease ◽

Therapeutic Potential ◽

Trichostatin A ◽

Hdac Inhibitors ◽

E3 Ligase ◽

Myeloma Cells ◽

Clonogenic Growth ◽

Pluripotency Genes

Abstract Recent studies have shown that binding of immune modulatory drugs (IMiDs)R lenalidomide and pomalidomide (Pom) to the CRBN-CRL4 E3 ubiquitin ligase complex leads to degradation of IKZF1 and IKZF3, which in turn mediates anti-proliferative effects on myeloma cells and enhance IL2 expression by T cells. However as the drug-induced IKZF1 degradation is proteasome-mediated, this mechanism does not explain the apparent paradox that IMiDs mediate synergistic anti-myeloma effects with proteasome inhibitors in the clinic. In order to better understand how MM cells may resist potent IMiDs such as Pom, we examined the clonogenic growth properties of residual MM cells following Pom exposure. Surprisingly, residual MM cell lines and primary MM cells following Pom exposure exhibit paradoxically enhanced clonogenic growth in culture. Human MM cells persisting after Pom exposure also exhibit greater capacity for growth in vivo. Enhanced clonogenic growth was associated with increased expression of embryonal stem cell genes such as SOX2 and RNAi-mediated inhibition of SOX2 abrogated Pom-induced enrichment of clonogenic potential. We hypothesized that as with CBRN/IKZF1-mediated effects, the induction of ES/pluripotency genes in Pom-exposed cells may be related to degradation of repressors of gene transcription. Recent studies have identified MBD3 as a critical component of the pluripotency repressor complex. Pom-exposure led to ubiquitin and proteasome-mediated degradation of MBD3 and RNAi-mediated inhibition of MBD3 led to induction of pluripotency genes by MM cells. As expected, loss of CRBN abrogates the capacity of Pom to mediate degradation of IKZF1. Surprisingly, Pom-mediated degradation of MBD3, enrichment of ES genes and enhancement of clonogenic growth was independent of CRBN as it was observed in MM1s-R10R cells with genomic loss of CRBN, and was not impacted by RNAi-mediated inhibition of CRBN. RNAi-mediated inhibition of IKZF1 also does not lead to enrichment of ES genes and does not phenocopy the effects of MBD3 depletion. Residual MM cells in patients (n=2) treated with Pom also revealed marked depletion of MBD3 protein as well as enrichment of ES gene transcripts. Taken together, these data identify a CRBN/IKZF1-independent pathway for Pom-induced depletion of MBD3 and enrichment of pluripotency genes. Pre-exposure to proteasome inhibitor MG132 abrogated Pom-mediated loss of MBD3 and enrichment of ES genes. Similar results were obtained following treatment with Trichostatin A (TSA) and Romidepsin (FK228), which also inhibited Pom-induced depletion of MBD3. Therefore concurrent therapy of IMiDs with proteasome or HDAC inhibitors may mediate synergistic anti-tumor effects by abrogating adverse effects of Pom exposure on clonogenic growth of residual cells. In order to further dissect the underlying mechanism of Pom-induced degradation of MBD3 in MM cells, we hypothesized engagement of another E3 ligase complex other than CRBN. We show that Pom-induced degradation of MBD3 depends on TRIM27/29 E3 ligase complex, known to be overexpressed in MM plasma cells. Accordingly, RNAi-mediated downregulation of TRIM27/29 inhibits Pom-induced MBD3 depletion and enrichment of clonogenic growth. In summary, these data identify a novel CRBN-independent, TRIM27/29 E3 ligase-dependent pathway for degradation of MDB3 engaged by Pomalidomide, which contributes to the biology of residual MM cells via enrichment of ES genes following exposure to these drugs in vitro/in vivo and provides a novel mechanism for observed synergy with proteasome and HDAC inhibitors. Targeting these pathways may be essential to enhance the therapeutic potential of IMiDs and minimize residual disease in MM. Disclosures No relevant conflicts of interest to declare.

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CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy

Cells ◽

10.3390/cells9061332 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1332

Author(s):

Ssu-Ju Fu ◽

Meng-Chun Hu ◽

Yi-Jheng Peng ◽

Hsin-Yu Fang ◽

Cheng-Tsung Hsiao ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Chloride Channels ◽

Therapeutic Potential ◽

Genetic Diseases ◽

Expression System ◽

E3 Ubiquitin Ligase ◽

E3 Ligase ◽

Proteasomal Degradation ◽

Loss Of Function ◽

Ring E3 Ligase

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis.

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Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2019.03.002 ◽

2019 ◽

Vol 153 (2) ◽

pp. 425-435 ◽

Cited By ~ 12

Author(s):

Isidre Felip ◽

Cristian Pablo Moiola ◽

Cristina Megino-Luque ◽

Carlos Lopez-Gil ◽

Silvia Cabrera ◽

...

Keyword(s):

Endometrial Cancer ◽

Anticancer Drug ◽

Therapeutic Potential

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Palbociclib Promotes Dephosphorylation of NPM/B23 at Threonine 199 and Inhibits Endometrial Cancer Cell Growth

Cancers ◽

10.3390/cancers11071025 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1025

Author(s):

Chiao-Yun Lin ◽

Li-Yu Lee ◽

Tzu-Hao Wang ◽

Cheng-Lung Hsu ◽

Chia-Lung Tsai ◽

...

Keyword(s):

Endometrial Cancer ◽

Cancer Cells ◽

Therapeutic Potential ◽

Combined Treatment ◽

Clinical Specimen ◽

Tumor Model ◽

Incidence Rates ◽

Cancer Cell Growth ◽

Antiproliferative Effects ◽

Er Positive

Endometrial cancer incidence rates are growing, especially in countries with rapid socioeconomic transitions. Despite recent advances in chemotherapy, hormone therapy, and targeted therapy, advanced/recurrent disease remains a clinical challenge. Palbociclib—a selective inhibitor of cyclin-dependent kinases (CDK) 4/6—has therapeutic potential against estrogen receptor (ER)-positive and HER2-negative breast cancer. However, the question as to whether it can be clinically useful in endometrial cancer remains open. Here, we show that combined treatment with palbociclib and megesterol acetate exerts synergistic antiproliferative effects against endometrial cancer cells. Treatment of cancer cells with palbociclib suppressed NPM/B23 phosphorylation at threonine 199 (Thr199). We further demonstrated that CDK6 acts as a NPM/B23 kinase. Palbociclib-induced NPM/B23 dephosphorylation sensitized endometrial cancer cells to megesterol acetate through the upregulation of ERα expression. Immunohistochemistry revealed an overexpression of phospho-NPM/B23 (Thr199) in human endometrial cancer, and phospho-NPM/B23 (Thr199) expression levels were inversely associated with Erα in clinical specimen. In a xenograft tumor model, the combination of palbociclib and megesterol acetate successfully inhibited tumor growth. Taken together, our data indicate that palbociclib promoted NPM/B23 dephosphorylation at Thr199—an effect mediated by disruption of CDK6 kinase activity. We conclude that palbociclib holds promise for the treatment of endometrial cancer when used in combination with megesterol acetate.

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Dinaciclib, a Bimodal Agent Effective against Endometrial Cancer

Cancers ◽

10.3390/cancers13051135 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1135

Author(s):

David Howard ◽

David James ◽

Kate Murphy ◽

Jezabel Garcia-Parra ◽

Belen Pan-Castillo ◽

...

Keyword(s):

Cell Cycle ◽

Endometrial Cancer ◽

Cell Lines ◽

Cell Cycle Progression ◽

Kinase Inhibitors ◽

Therapeutic Potential ◽

Early Stage ◽

Type I ◽

Cycle Progression ◽

Carboxy Terminal

Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II–IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.

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