Targeting progesterone signaling prevents metastatic ovarian cancer

Kim, Olga; Park, Eun Young; Kwon, Sun Young; Shin, So Jin; Emerson, Robert E.; Shin, Yong‐Cheol; DeMayo, Francesco J.; Lydon, John P.; Coffey, Donna; Hawkins, Shannon M.; Quilliam, Lawrence A.; Cheon, Dong Joo; Fernández, Facundo M.; Nephew, Kenneth P.; Karpf, Adam R.; Widschwendter, Martin; Sood, Anil K.; Bast, Robert C.; Godwin, Andrew K.; Miller, Kathy D.; Cho, Chi Heum; Kim, Jaeyeon

doi:10.1073/pnas.2013595117

Cited by 31 publications

(23 citation statements)

References 106 publications

(145 reference statements)

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“…We used five sets of different mouse models to test and compare the efficacies: PE04 control cells ± CDDP; ZIP4-KO ± CDDP, HDAC4-KD ± CDDP, a pan-HDACi (PANO) ± CDDP, and a selective HDAC4/5 inhibitor, LMK-235 ± CDDP. In all five pairs of comparisons, even though single gene KO or KD or single HDACi significant increased mouse survival times, combination with CDDP clearly had significant additional benefit, extending additional mouse survival times ranging from 45 to 96 days (~4.5-9.6 human years [106]), supporting our overall hypothesis. It is important to note that CDDP treatment eventually enhanced expression of ZIP4, HDAC4, or ALDA1 in tumors from different mouse groups, supporting the idea that CDDP has the ability to induce CSCs [95].…”

Section: Discussionsupporting

confidence: 74%

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

Fan

Wang

et al. 2021

Cancers

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We have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 selectively upregulated HDAC IIa HDACs, with little or no effect on HDACs in other classes. HDAC4 knockdown (KD) and LMK-235 inhibited spheroid formation in vitro and tumorigenesis in vivo, with hypoxia inducible factor-1 alpha (HIF1α) and endothelial growth factor A (VEGFA) as functional downstream mediators of HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1α were involved in regulating secreted VEGFA in HGSOC cells. Furthermore, we tested our hypothesis that co-targeting CSC via the ZIP4-HDAC4 axis and non-CSC using CDDP is necessary and highly effective by comparing the effects of ZIP4-knockout/KD, HDAC4-KD, and HDACis, in the presence or absence of CDDP on tumorigenesis in mouse models. Our results showed that the co-targeting strategy was highly effective. Finally, data from human HGSOC tissues showed that ZIP4 and HDAC4 were upregulated in a subset of recurrent tumors, justifying the clinical relevance of the study. In summary, our study provides a new mechanistic-based targeting strategy for HGSOC.

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Section: Discussionsupporting

confidence: 74%

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

Fan

Wang

et al. 2021

Cancers

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“…Effects on serum P4 levels were conflicting (Barnhart et al 2004;Niinimäki et al 2009;Zhu et al 2020). Mifepristone is a well-established PR antagonist (Ho et al 2002;Kim et al 2020).…”

Section: 5mentioning

confidence: 99%

“…Chemicals may also have multiple biological effects in vivo that may overshadow the effects of increased hormone levels or which make it hard to separate effects due to steroidogenesis vs. receptor agonism. For example, in our literature review of chemicals with high potency/efficacy, mifepristone both increased P4 and is considered a strong PR antagonist (Chwalisz 1994;Ho et al 2002;Kim et al 2020), thus the effects of increased P4 levels on the PR may be blocked. HPTE increased E2, but is considered a strong ER agonist (Hewitt and Korach 2011), so it was difficult to tell which of the relevant outcomes observed were related to ER agonism vs. steroidogenesis.…”

Section: Strengths and Limitations Of In Vitro Data From The H295r Steroidogenesis Assaymentioning

confidence: 99%

Application of an in Vitro Assay to Identify Chemicals That Increase Estradiol and Progesterone Synthesis and Are Potential Breast Cancer Risk Factors

Cardona

Rudel

2021

Environ Health Perspect

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BACKGROUND: Established breast cancer risk factors, such as hormone replacement therapy and reproductive history, are thought to act by increasing estrogen and progesterone (P4) activity. OBJECTIVE: We aimed to use in vitro screening data to identify chemicals that increase the synthesis of estradiol (E2) or P4 and evaluate potential risks. METHOD: Using data from a high-throughput (HT) in vitro steroidogenesis assay developed for the U.S. Environmental Protection Agency (EPA) ToxCast program, we identified chemicals that increased estradiol (E2-up) or progesterone (P4-up) in human H295R adrenocortical carcinoma cells. We prioritized chemicals by their activity. We compiled in vivo studies and assessments about carcinogenicity and reproductive/developmental (repro/dev) toxicity. We identified exposure sources and predicted intakes from the U.S. EPA's ExpoCast. RESULTS: We found 296 chemicals increased E2 (182) or P4 (185), with 71 chemicals increasing both. In vivo data often showed effects consistent with this mechanism. Of the E2-and P4-up chemicals, about 30% were likely repro/dev toxicants or carcinogens, whereas only 5-13% were classified as unlikely. However, most of the chemicals had insufficient in vivo data to evaluate their effects. Of 45 chemicals associated with mammary gland effects, and also tested in the H294R assay, 29 increased E2 or P4, including the well-known mammary carcinogen 7,12-dimethylbenz(a)anthracene. E2-and P4-up chemicals include pesticides, consumer product ingredients, food additives, and drinking water contaminants. DISCUSSION: The U.S. EPA's in vitro screening data identified several hundred chemicals that should be considered as potential risk factors for breast cancer because they increased E2 or P4 synthesis. In vitro data is a helpful addition to current toxicity assessments, which are not sensitive to mammary gland effects. Relevant effects on the mammary gland are often not noticed or are dismissed, including for 2,4-dichlorophenol and cyfluthrin. Fifty-three active E2-up and 59 active P4-up chemicals that are in consumer products, food, pesticides, or drugs have not been evaluated for carcinogenic potential and are priorities for study and exposure reduction.

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“…It is of importance to discover and intervene risk factors via effective cancer prevention during cancer progression ( 4 ). Currently, various driver genes have been found.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis Identifies Potential Ferroptosis-Associated mRNA Therapeutic Targets in Ovarian Cancer

Zhang

Huang

et al. 2021

Front. Med.

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Objective: This study aimed to explore ferroptosis-related mRNAs as potential therapeutic targets for ovarian cancer treatment.Methods: Molecular subtypes were classified based on ferroptosis-related mRNAs via ConsensusClusterPlus package. The differences in prognosis, stromal score, immune score, immune function, and immune checkpoints were assessed between subtypes. Small molecular drugs were predicted via the CMap database. The sensitivity to chemotherapy drugs was estimated through the GDSC. A LASSO Cox regression model was conducted via the glmnet package, followed by a nomogram model.Results: Based on ferroptosis mRNA expression profile, two molecular subtypes (C1 and C2) were classified, with distinct clinical outcomes. C1 subtype exhibited higher stromal score, immune cell score (T helper, Treg, neutrophil) and immune function (APC co-inhibition, parainflammation and Type II IFN response). Higher mRNA expression levels of immune checkpoints (like PDCD1) were found in C1 than C2. Potential small molecular drugs (PI3K and mTOR inhibitors) were found for treatment of ovarian cancer. C1 was more sensitive to eight chemotherapy drugs (A.443654, AZD.0530, AZD6482, AZD7762, AZD8055, BAY.61.3606, Bicalutamide, and CGP.60474). A 15-ferroptosis-related mRNA signature was developed, which could robustly and independently predict the outcomes. Moreover, a nomogram was established combining the signature and age, which could intuitively and accurately predict the 5-year overall survival probability.Conclusion: Our study characterized two ferroptosis-related subtypes with distinct prognosis and tumor immune features, which could assist clinicians make decisions and individual therapy. Moreover, 15 ferroptosis-related mRNAs were identified, which could become potential therapeutic targets for ovarian cancer.

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Targeting progesterone signaling prevents metastatic ovarian cancer

Cited by 31 publications

References 106 publications

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

Application of an in Vitro Assay to Identify Chemicals That Increase Estradiol and Progesterone Synthesis and Are Potential Breast Cancer Risk Factors

Comprehensive Analysis Identifies Potential Ferroptosis-Associated mRNA Therapeutic Targets in Ovarian Cancer

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