The Role of GDF15 in Regulating the Canonical Pathways of the Tumor Microenvironment in Wild-Type p53 Ovarian Tumor and Its Response to Chemotherapy

Izaguirre, Daisy I.; Ng, Chun Wai; Kwan, Suet Yan; Kun, Eucharist; Tsang, Yvonne T.M.; Gershenson, David M.; Wong, Kwong-Kwok

doi:10.3390/cancers12103043

Cited by 9 publications

(4 citation statements)

References 41 publications

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“…Activation of the p53 was also demonstrated to be responsible for GDF15 expression [87]. Recent evidence showed that GDF15 modulates the canonical pathways in wild‐type p53 ovarian cancer cells and contributes to chemoresistance [88]. In the present study, we used the NUGC‐3 gastric cancer cells belonging to the p53‐mutant cell line [89].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15

Wang,

Chang,

Liu

et al. 2023

The FEBS Journal

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Gastric neoplasm is a high‐mortality cancer worldwide. Chemoresistance is the obstacle against gastric cancer treatment. Mitochondrial dysfunction has been observed to promote malignant progression. However, the underlying mechanism is still unclear. The mitokine growth differentiation factor 15 (GDF15) is a significant biomarker for mitochondrial disorder and is activated by the integrated stress response (ISR) pathway. The serum level of GDF15 was found to be correlated with the poor prognosis of gastric cancer patients. In this study, we found that high GDF15 protein expression might increase disease recurrence in adjuvant chemotherapy‐treated gastric cancer patients. Moreover, treatment with mitochondrial inhibitors, especially oligomycin (a complex V inhibitor) and salubrinal (an ISR activator), respectively, was found to upregulate GDF15 and enhance cisplatin insensitivity of human gastric cancer cells. Mechanistically, it was found that the activating transcription factor 4‐C/EBP homologous protein pathway has a crucial function in the heightened manifestation of GDF15. In addition, reactive oxygen species‐activated general control nonderepressible 2 mediates the oligomycin‐induced ISR, and upregulates GDF15. The GDF15–glial cell‐derived neurotrophic factor family receptor a‐like–ISR–cystine/glutamate transporter‐enhanced glutathione production was found to be involved in cisplatin resistance. These results suggest that mitochondrial dysfunction might enhance cisplatin insensitivity through GDF15 upregulation, and targeting mitokine GDF15–ISR regulation might be a strategy against cisplatin resistance of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15

Wang,

Chang,

Liu

et al. 2023

The FEBS Journal

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“…At present, the main chemotherapeutic drugs for ovarian cancer are cisplatin, paclitaxel and so on 26 . However, due to the emergence of drug resistance in ovarian cancer, the therapeutic effect of cisplatin is less potent, and there is still the high mortality of ovarian cancer 27 .…”

Section: Discussionmentioning

confidence: 99%

Bioactive Hexapeptide Reduced the Resistance of Ovarian Cancer Cells to DDP by Affecting HSF1/HSP70 Signaling Pathway

Guo

Liu

et al. 2021

J. Cancer

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Ovarian cancer is the leading cause of death in gynecologic malignancies. Ovarian cancer as a metastatic malignant tumor is highly recurrent and prone to drug resistance. Bioactive peptides are an emerging area of biomedical research in reducing resistance of tumor cell to drugs. In this paper, we investigated the effects and mechanisms of bioactive hexapeptide (PGPIPN) derived in milk protein on the sensitivity of ovarian cancer cells to cis-dichlorodiammine platinum (DDP). Human ovarian cancer cell lines (SKOV3 and COC1), their DDP-resistant sublines (SKOV3/DDP and COC1/DDP) and human primary ovarian cancer cells were cultured in vitro under the combined treatment of DDP (close to IC50) and different concentrations of PGPIPN. The viabilities, apoptosis and cell cycle changes were respectively measured by WST-8 and flow cytometry. The mRNA and protein expression levels of HSF1, HSP70, MDR1, ERCC1 and β-actin gene were respectively assayed by RT-qPCR and western blotting. The results showed that PGPIPN significantly increased the sensitivity of human ovarian cancer cells to DDP in inhibiting viability and inducing apoptosis in vitro. But the effects in sensitive cells were lower than DDP-resistant cells. PGPIPN significantly changed the cell cycles in all human ovarian cancer cells, which leaded to a significant increase in the percentage of cells blocked at G2/M phase and decrease the percentage of cells at G1 phases in a dose-dependent manner. PGPIPN affected the expression levels of HSF1, HSP70, MDR1 and ERCC1 genes. Compared with cells in DDP treatment alone, the expression levels of HSF1 and HSP70 in human ovarian cancer cells treated with DDP and PGPIPN together significantly decreased in dose-dependent manner. PGPIPN significantly decreased MDR1 and ERCC1 of drug-resistant ovarian cancer cell lines and human primary ovarian cancer cell in a dose-dependent manner. Pifithrin-μ (PFTμ, HSP70 inhibitor) decreased or removed the effects of peptide in increasing the sensitivity of ovarian cancer cells to DDP. This suggests that PGPIPN enhanced the sensitivity of ovarian cancer cells to DDP partially via reducing the activity of HSF1/HSP70 signaling pathway, thus inducing cell apoptosis and decreasing repairment of DNA damage.

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“…RNA-seq was performed at the MD Anderson Cancer Center Advanced Technology Genomics Core Laboratory as previously described [ 22 , 30 ]. Total RNA from the same 14 frozen WGS samples was prepared using an RNeasy Mini Kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors

Wong

Bateman

et al. 2022

J Transl Med

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Background Low-grade serous ovarian cancer (LGSOC) is a rare disease that occurs more frequently in younger women than those with high-grade disease. The current treatment is suboptimal and a better understanding of the molecular pathogenesis of this disease is required. In this study, we compared the proteogenomic analyses of LGSOCs from short- and long-term survivors (defined as < 40 and > 60 months, respectively). Our goal was to identify novel mutations, proteins, and mRNA transcripts that are dysregulated in LGSOC, particularly in short-term survivors. Methods Initially, targeted sequencing of 409 cancer-related genes was performed on 22 LGSOC and 6 serous borderline ovarian tumor samples. Subsequently, whole-genome sequencing analysis was performed on 14 LGSOC samples (7 long-term survivors and 7 short-term survivors) with matched normal tissue samples. RNA sequencing (RNA-seq), quantitative proteomics, and phosphoproteomic analyses were also performed. Results We identified single-nucleotide variants (SNVs) (range: 5688–14,833 per sample), insertion and deletion variants (indels) (range: 880–1065), and regions with copy number variants (CNVs) (range: 62–335) among the 14 LGSOC samples. Among all SNVs and indels, 2637 mutation sites were found in the exonic regions. The allele frequencies of the detected variants were low (median12%). The identified recurrent nonsynonymous missense mutations included KRAS, NRAS, EIF1AX, UBR5, and DNM3 mutations. Mutations in DNM3 and UBR5 have not previously been reported in LGSOC. For the two samples, somatic DNM3 nonsynonymous missense mutations in the exonic region were validated using Sanger sequencing. The third sample contained two missense mutations in the intronic region of DNM3, leading to a frameshift mutation detected in RNA transcripts in the RNA-seq data. Among the 14 LGSOC samples, 7754 proteins and 9733 phosphosites were detected by global proteomic analysis. Some of these proteins and signaling pathways, such as BST1, TBXAS1, MPEG1, HBA1, and phosphorylated ASAP1, are potential therapeutic targets. Conclusions This is the first study to use whole-genome sequencing to detect somatic mutations in LGSOCs with matched normal tissues. We detected and validated novel mutations in DNM3, which were present in 3 of the 14 samples analyzed. Additionally, we identified novel indels, regions with CNVs, dysregulated mRNA, dysregulated proteins, and phosphosites that are more prevalent in short-term survivors. This integrated proteogenomic analysis can guide research into the pathogenesis and treatment of LGSOC.

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The Role of GDF15 in Regulating the Canonical Pathways of the Tumor Microenvironment in Wild-Type p53 Ovarian Tumor and Its Response to Chemotherapy

Cited by 9 publications

References 41 publications

Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15

Mitochondrial dysfunction decreases cisplatin sensitivity in gastric cancer cells through upregulation of integrated stress response and mitokine GDF15

Bioactive Hexapeptide Reduced the Resistance of Ovarian Cancer Cells to DDP by Affecting HSF1/HSP70 Signaling Pathway

Integrated multi-omic analysis of low-grade ovarian serous carcinoma collected from short and long-term survivors

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