Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer

Borneman, Rebecca M.; Gavin, Elaine; Musiyenko, Alla; Richter, Wito; Lee, Kevin J.; Crossman, David K.; Andrews, Joel; Wilhite, Annelise; McClellan, Steven; Aragon, Ileana; Ward, Antonio; Chen, Xi; Keeton, Adam B.; Berry, Kristy; Piazza, Gary A.; Scalici, Jennifer; Silva, Luciana Madeira da

doi:10.1186/s13048-022-01050-9

Cited by 11 publications

(8 citation statements)

References 56 publications

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“…13,14,25 While PDE10A inhibition exerts antiovarian cancer effect via mediating both cAMP/PKA and cGMP/PKG signaling and subsequently leads to inhibition of β-catenin signaling and decreased activation of the MAPK and AKT (protein kinase B) pathways. 35 In the current study, we found that PDE10A contributes to cardiomyocyte atrophy induced by DOX. Previously, we also showed that PDE10A contributes to cardiomyocyte pathological hypertrophy induced by chronic pressure overload or neurohormonal stimulation but not physiological hypertrophy.…”

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

“…34 During the preparation of this article, a new published study reported that PDE10A inhibition decreases ovarian cancer growth and induces apoptosis, which supports our observation in ovarian cancer cells and in nude mice xenograft. 35 In addition, a PDE10A single-nucleotide polymorphism variant in a noncoding exon is associated with the risk of tobacco-induced developing non-small-cell lung cancer. 36 A Pro360Ala mutation of PDE10A has been shown to play a potential oncogenic role in non-small-cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

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PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Chen

et al. 2023

Circulation Research

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BACKGROUND: Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX. METHODS: We used global PDE10A KO (knockout) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies. RESULTS: We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA- (protein kinase A) and cGMP/PKG-dependent signaling. CONCLUSIONS: Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Chen

et al. 2023

Circulation Research

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“…Recently, the efficacy and clinical utility of biomarker-driven targeted therapy have been suggested, warranting further exploration in phase 3 trials (details are listed in Supplementary Table S4) [37][38][39][40]. With recent advances in -omics tools, it is the right time for this endeavor.…”

Section: Discussion and Future Challengesmentioning

confidence: 99%

Spotlight on New Hallmarks of Drug-Resistance towards Personalized Care for Epithelial Ovarian Cancer

Frezzini,

Lonardi

2024

Cells

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Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Despite the latest advances, a major clinical issue in EOC is the disappointing prognosis related to chemoresistance in almost one-third of cases. Drug resistance relies on heterogeneous cancer stem cells (CSCs), endowed with tumor-initiating potential, leading to relapse. No biomarkers of chemoresistance have been validated yet. Recently, major signaling pathways, micro ribonucleic acids (miRNAs), and circulating tumor cells (CTCs) have been advocated as putative biomarkers and potential therapeutic targets for drug resistance. However, further investigation is mandatory before their routine implementation. In accordance with the increasing rate of therapeutic efforts in EOC, the need for biomarker-driven personalized therapies is growing. This review aims to discuss the emerging hallmarks of drug resistance with an in-depth insight into the underlying molecular mechanisms lacking so far. Finally, a glimpse of novel therapeutic avenues and future challenges will be provided.

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“…In addition to suppressing β-catenin transcriptional activity, PDE10 inhibitors have been reported to activate dendritic cells and increase T-cell tumor invasion, suggesting the potential to generate anticancer immune responses [85,86]. ADT-061 (aka MCI-030) was also reported to inhibit the growth of ovarian cancer cells by suppressing Wnt/β-catenin and RAS/MAPK signaling [87], both of which may result from its PDE10 inhibitory activity as previously reported for known PDE10 inhibitors [82], possibly by a cGMP/PKG dependent mechanism to block RAS activation [88]. Alternatively, the inhibitory effect on RAS/MAPK signaling may result from a distinct effect on RAS, as suggested by previous studies of sulindac [19,26].…”

Section: Role Of Pde10 In Regulating Crc Cell Growthmentioning

confidence: 99%

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

Ramesh,

Johnson,

Fadlalla

et al. 2023

Self Cite

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<p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"><span lang="EN-US" style="font-size: 10pt; font-family: arial, helvetica, sans-serif;">Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.</span></p>

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Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer

Cited by 11 publications

References 56 publications

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Spotlight on New Hallmarks of Drug-Resistance towards Personalized Care for Epithelial Ovarian Cancer

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

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