Identifying the role of transmembrane protein TMEM205 in promoting platinum resistance in ovarian cancer through exosomal efflux of platinum agents

2021 ◽  
Vol 162 ◽  
pp. S173
Author(s):  
Corinne Calo ◽  
Kalpana Deepa Priya Dorayappan ◽  
Vincent Wagner ◽  
Marissa Werner ◽  
Qi-En Wang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Transmembrane Protein ◽  
Platinum Resistance ◽  
Platinum Agents

scholarly journals Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A is Mediated by Replication Protein A in Ovarian Cancer

2020 ◽  
Author(s):  
Shruthi Sriramkumar ◽  
Timothy D. Matthews ◽  
Ahmed H. Ghobashi ◽  
Samuel A. Miller ◽  
Pamela S. VanderVere-Carozza ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Excision Repair ◽  
Protein A ◽  
Replication Protein A ◽  
Replication Protein ◽  
Platinum Resistance ◽  
Platinum Agents ◽  
Chromatin Modifiers

AbstractPlatinum resistance is a common occurrence in high grade serous ovarian cancer (HGSOC) and a major cause of OC deaths. Platinum agents form DNA crosslinks, which activate nucleotide excision repair (NER), fanconi anemia (FA) and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in OC and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in OC is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in OC cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A (RPA), involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impaired the activation of the G2/M DNA damage checkpoint and reduced the ability of OC cells to repair platinum DNA damage. Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of OC to standard chemotherapy regimens.

scholarly journals CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0251079
Author(s):  
Yoshiko Oyama ◽  
Shogo Shigeta ◽  
Hideki Tokunaga ◽  
Keita Tsuji ◽  
Masumi Ishibashi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
The Cancer Genome Atlas ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Nucleosome Remodeling ◽  
Platinum Sensitivity ◽  
Mdr1 Expression ◽  
Platinum Agents

Platinum sensitivity is an important prognostic factor in patients with ovarian cancer. Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a core member of the nucleosome remodeling and deacetylase complex, which functions as a chromatin remodeler. Emerging evidence indicates that CHD4 could be a potential therapeutic target for cancer therapy. The purpose of this study was to clarify the role of CHD4 in ovarian cancer and investigate its therapeutic potential focusing on platinum sensitivity. In an analysis of the Cancer Genome Atlas ovarian cancer dataset, CHD4 gene amplification was associated with worse overall survival. CHD4 mRNA expression was significantly higher in platinum-resistant samples in a subsequent clinical sample analysis, suggesting that CHD4 overexpression conferred platinum resistance to ovarian cancer cells, resulting in poor patient survival. In concordance with these findings, CHD4 knockdown enhanced the induction of apoptosis mediated by cisplatin in ovarian cancer cells TOV21G and increased cisplatin sensitivity in multiple ovarian cancer cells derived from different subtypes. However, CHD4 knockdown did not affect the expression of RAD51 or p21, the known targets of CHD4 in other cancer types that can modulate platinum sensitivity. Knockdown and overexpression assays revealed that CHD4 positively regulated the expression of multi-drug transporter MDR1 and its coding protein p-glycoprotein. In addition, a first-in-class CHD4/SMARCA5 inhibitor ED2-AD101 showed synergistic interactions with cisplatin. Our findings suggest that CHD4 mediates platinum sensitivity by modulating MDR1 expression in ovarian cancer. Further, CHD4 suppression has a potential to be a novel therapeutic strategy in combination with platinum agents.

scholarly journals Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer

2016 ◽  
Vol 142 (3) ◽  
pp. 539-547 ◽  
Author(s):  
Maria de Leon ◽  
Horacio Cardenas ◽  
Edyta Vieth ◽  
Robert Emerson ◽  
Matthew Segar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Transmembrane Protein ◽  
Platinum Resistance

scholarly journals Novel epigenetic-metabolic inhibitor combination treatment blocks platinum-induced ovarian cancer stem cell enrichment

2021 ◽  
Author(s):  
Riddhi Sood ◽  
Sikai Xiao ◽  
Shruthi Sriramkumar ◽  
Christiane Hassel ◽  
Kenneth P. Nephew ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Ovarian Cancer ◽  
Dna Methyltransferases ◽  
Metabolic Inhibitor ◽  
Platinum Resistance ◽  
Dna Hypermethylation ◽  
Ovarian Cancer Stem Cells ◽  
Promoter Dna ◽  
Rate Limiting ◽  
Platinum Agents

AbstractHigh grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer. Platinum resistance is a common occurrence in HGSOC and a main cause of tumor relapse resulting in high patient mortality rates. Recurrent ovarian cancer is enriched in aldehyde dehydrogenase (ALDH)+ ovarian cancer stem cells (OCSCs), which are resistant to platinum agents. We demonstrated that acute platinum treatment induced a DNA damage-dependent decrease in BRCA1 levels throughBRCA1promoter DNA hypermethylation. In a parallel pathway associated with G2/M arrest, platinum treatment also induced an increase in expression ofNAMPT, the rate limiting regulator of NAD+production from the salvage pathway, and NAD+levels, the cofactor required for ALDH activity. Both decreased BRCA1 and increased NAD+levels were required for the platinum-induced enrichment of OCSCs, and inhibition of both DNA methyltransferases (DNMT) and NAMPT synergistically abrogated the platinum-induced increase in OCSCs. We conclude that these two separate pathways lead to platinum-induced OCSC enrichment, providing preclinical evidence that in the neoadjuvant setting, combining DNMT and NAMPT inhibitors with platinum has the potential to reduce OC reoccurrence.

scholarly journals c-MYC and Epithelial Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jeyshka M. Reyes-González ◽  
Pablo E. Vivas-Mejía
Keyword(s):  
Patient Outcome ◽  
Ovarian Cancer ◽  
Standard Of Care ◽  
Initial Response ◽  
Platinum Resistance ◽  
Therapy Regimen ◽  
Clinical Challenge ◽  
Tumor Types ◽  
Improve Patient

Ovarian cancer is the deadliest of gynecological malignancies with approximately 49% of women surviving 5 years after initial diagnosis. The standard of care for ovarian cancer consists of cytoreductive surgery followed by platinum-based combination chemotherapy. Unfortunately, despite initial response, platinum resistance remains a major clinical challenge. Therefore, the identification of effective biomarkers and therapeutic targets is crucial to guide therapy regimen, maximize clinical benefit, and improve patient outcome. Given the pivotal role of c-MYC deregulation in most tumor types, including ovarian cancer, assessment of c-MYC biological and clinical relevance is essential. Here, we briefly describe the frequency of c-MYC deregulation in ovarian cancer and the consequences of its targeting.

scholarly journals Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance

Oncotarget ◽  
2015 ◽  
Vol 6 (27) ◽  
pp. 23720-23734 ◽  
Author(s):  
Anil Belur Nagaraj ◽  
Peronne Joseph ◽  
Olga Kovalenko ◽  
Sareena Singh ◽  
Amy Armstrong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Critical Role ◽  
Platinum Resistance

scholarly journals Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Deepak Parashar ◽  
Anjali Geethadevi ◽  
Donna McAllister ◽  
Johnathan Ebben ◽  
Francis C. Peterson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cell ◽  
Cell Lines ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Transmembrane Protein ◽  
Acquired Resistance ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Dismal Prognosis

AbstractRecurrence of therapy-resistant tumors is a principal problem in solid tumor oncology, particularly in ovarian cancer. Despite common complete responses to first line, platinum-based therapies, most women with ovarian cancer recur, and eventually, nearly all with recurrent disease develop platinum resistance. Likewise, both intrinsic and acquired resistance contribute to the dismal prognosis of pancreatic cancer. Our previous work and that of others has established CLPTM1L (cleft lip and palate transmembrane protein 1-like)/CRR9 (cisplatin resistance related protein 9) as a cytoprotective oncofetal protein that is present on the tumor cell surface. We show that CLPTM1L is broadly overexpressed and accumulated on the plasma membrane of ovarian tumor cells, while weakly or not expressed in normal tissues. High expression of CLPTM1L is associated with poor outcome in ovarian serous adenocarcinoma. Robust re-sensitization of resistant ovarian cancer cells to platinum-based therapy was achieved using human monoclonal biologics inhibiting CLPTM1L in both orthotopic isografts and patient-derived cisplatin resistant xenograft models. Furthermore, we demonstrate that in addition to cell-autonomous cytoprotection by CLPTM1L, extracellular CLPTM1L confers resistance to chemotherapeutic killing in an ectodomain-dependent fashion, and that this intercellular resistance mechanism is inhibited by anti-CLPTM1L biologics. Specifically, exosomal CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines conferred resistance to cisplatin in drug-sensitive parental cell lines. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patients’ serum with increasing abundance upon chemotherapy treatment. These findings have encouraging implications for the use of anti-CLPTM1L targeted biologics in the treatment of therapy-resistant tumors.

The Role of Cytoreductive/Debulking Surgery in Ovarian Cancer

2008 ◽  
Vol 6 (8) ◽  
pp. 803-811 ◽  
Author(s):  
Mark T. Wakabayashi ◽  
Paul S. Lin ◽  
Amy A. Hakim
Keyword(s):  
Ovarian Cancer ◽  
Median Survival ◽  
The United States ◽  
Disease Free Interval ◽  
The Past ◽  
Initial Surgery ◽  
Platinum Agents ◽  
Disease Free ◽  
Interval Cytoreduction

Ovarian cancer is the fifth most common cause of cancer-related death among women in the United States, although the median survival of patients has been increasing over the past few decades. In patients with epithelial ovarian cancer, chemotherapy has increased survival. Platinum agents combined with taxanes have become standard treatment. Intraperitoneal chemotherapy has also increased survival. Cytoreductive surgery to optimally debulk a tumor or, ideally, remove any gross disease has also been shown to increase survival. Each 10% increase in cytoreduction correlates with a 5.5% increase in median survival. The ability to successfully perform optimal cytoreduction ranges from 20% to 90%. Many institutions have recently begun to perform aggressive/ultraradical procedures to achieve this result. Interval cytoreduction may also benefit patients whose initial surgery is suboptimal, especially if the first procedure was performed by a surgeon unfamiliar with the disease. Secondary cytoreduction can increase survival in patients with low-volume disease and a long disease-free interval. All of these procedures should be performed by a specialist trained in ovarian cancer surgery.

scholarly journals A Retrospective Cross-Sectional Cohort Trial Assessing the Prevalence of MTHFR Polymorphisms and the Influence of Diet on Platinum Resistance in Ovarian Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5215
Author(s):  
Caitlin Phillips-Chavez ◽  
Jermaine Coward ◽  
Michael Watson ◽  
Janet Schloss
Keyword(s):  
Ovarian Cancer ◽  
Survival Rate ◽  
Serum Folate ◽  
Platinum Resistance ◽  
Aberrant Methylation ◽  
Dietary Zinc ◽  
Mthfr Polymorphism ◽  
Mthfr Polymorphisms ◽  
Platinum Sensitivity

Ovarian cancer has the lowest survival rate in gynaecologic malignancies with a 5-year survival rate of 43%. Platinum resistance is one of the main drivers of ovarian cancer mortality, of which aberrant methylation has been cited as a significant contributor. Understanding the essential role of the methylenetetrahydrofolate reductase enzyme (MTHFR) on DNA synthesis and repair, and how nutrient status can vastly affect its performance, led to the investigation of MTHFR status and dietary influence on platinum response in epithelial ovarian cancer (EOC) patients. Twenty-five adult female patients who completed first-line platinum-based chemotherapy for primary ovarian cancer were selected from Icon Cancer Centres in Australia. Participants were grouped based on platinum response. A full medical and family history, food frequency questionnaire and single blood test were completed, testing for MTHFR polymorphisms, serum folate, serum and active B12 and homocysteine levels. Nineteen of twenty-five participants had an MTHFR polymorphism. Of those, 20% were compound heterozygous, 12% were heterozygous C677T (CT), 4% homozygous C677T, 12% homozygous A1298C and 28% were heterozygous A1298C (AC). Statistically significant associations were found between dietary zinc (p = 0.0086; 0.0030; 0.0189) and B12 intakes in CT genotypes (p = 0.0157; 0.0030; 0.0068) indicating that zinc or vitamin B12 intakes below RDI were associated with this genotype. There were strong associations of vitamin B6 intakes in AC genotypes (p = 0.0597; 0.0547; 0.0610), and dietary folate in compound heterozygotes with sensitive and partially sensitive disease (p = 0.0627; 0.0510). There were also significant associations between serum folate (p = 0.0478) and dietary B12 (p = 0.0350) intakes above RDI and platinum sensitivity in wild-types as well as strong associations with homocysteine levels (p = 0.0886) and zinc intake (p = 0.0514). Associations with dietary B12 (p = 0.0514) and zinc intakes (p = 0.0731) were also strong in resistant wild types. Results indicate that dietary zinc, B12 and B6 intakes may be associated with platinum sensitivity dependent on MTHFR genotype. These results require further research to clarify the dosages necessary to elicit a response; however, they provide a novel foundation for acknowledging the role of diet on treatment response in EOC.

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