Biguanides in combination with olaparib limits tumorigenesis of drug‐resistant ovarian cancer cells through inhibition of Snail

Wang, Qiong; López-Ozuna, Vanessa M.; Baloch, Tahira; Bithras, Joanne; Amin, Oreekha; Kessous, Roy; Kogan, Liron; Laskov, Ido; Yasmeen, Amber

doi:10.1002/cam4.2738

Cited by 13 publications

(12 citation statements)

References 41 publications

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“…At present, the difficulty of multiple tumor treatments is the resistance of relapse and chemotherapy. Studies have pointed out that EMT signaling pathway is an important mechanism for the development of ovarian tumor [5,29]. Studies have shown that the BMP4-mediated signaling pathway led to morphological changes in tumor cells and enhanced cell adhesion, migration, and invasion by inducing EMT [30].…”

Section: Discussionmentioning

confidence: 99%

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Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

et al. 2020

Bioscience Reports

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Objective: To investigate the specific function of long non-coding RNA HAL in serous ovarian cancer (SOC) and to further clarify the regulation of HAL on EMT pathway. Materials and methods: The expression of HAL and TWIST1 was detected by qRT-PCR. CCK8 assay, wound healing assay, transwell assay and flow cytometry were used to detect the HAL function on proliferation, migration, invasion and apoptosis in SOC cells. Western blot was used to calculate protein level of Vimentin, N-cadherin and E-cadherin. The effect of HAL on tumorigenesis of SOC was confirmed by xenograft nude mice model. Results: HAL was significantly decreased in SOC tissues and cells. Overexpression of HAL inhibited the proliferation, migration and invasion of SKOV3 cells, but promoted apoptosis. Furthermore, overexpression of HAL decreased the mRNA and protein levels of TWIST1 via a binding between HAL and TWIST1. Forced expression of TWIST1 reversed the inhibitory role of HAL on SOC cells’ migration and invasion. The in vivo tumor growth assay showed that HAL suppressed SOC tumorigenesis with inhibiting EMT pathway. Conclusions: Our research emphasized HAL acting as a tumor-inhibiting gene by regulating EMT signaling pathway, thus providing some novel experimental basis for clinical treatment of SOC.

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Section: Discussionmentioning

confidence: 99%

“…The standard initial treatment for SOC is tumor cell reduction followed by platinum or paclitaxel chemotherapy [4]. Despite such aggressive treatment, recurrence and metastasis rates remain high [5]. Although other diagnosis and treatment methods have improved the treatment effect of patients, the long-term survival rate is still worrying.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

et al. 2020

Bioscience Reports

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“…EMT was thought to be one of the manual mechanisms. EMT properties were reported to contribute to cell proliferation, invasion, migration, and metastasis in various malignant tumours [23,24]. These findings highlighted the clinical relevance of E2F4as in predicting the detrimental prognosis of ovarian cancer, and suggest the possibility of promoting tumour aggression through the regulation of EMT-related mechanisms [25].…”

Section: Discussionmentioning

confidence: 82%

Long Noncoding RNA E2F4as Promotes Progression and Predicts Patient Prognosis in Human Ovarian Cancer

Park

Kim

et al. 2020

Cancers

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(1) Background: LncRNAs could be a promising biomarker to predict the prognosis of various cancers. The significance of E2F4antisense lncRNA remains unclear in cancer. In this study, we examined the expression level of E2F4as in the serum of ovarian cancer patients and the functional role of E2F4as. (2) Methods: Serum samples were obtained from 108 OC patients and 32 normal patients to measure the expression of E2F4as in the serum. Ovarian cancer cells were used to investigate the role of E2F4as in cell proliferation, invasion, migration and apoptosis, and the expression of E2F4as was knocked down using RNA interference. In addition, E2F4as knockdown cell lines were used in in vivo experiments. (3) Results: The expression of E2F4as was significantly higher in the serum of OC patients than in that of control patients (p < 0.05). The knockdown of E2F4as in ovarian cancer cells led to a decrease in cell proliferation, invasion and migration and an increase in apoptosis. E2F4as knockdown also reduced the expression of epithelium–mesenchymal metastasis (EMT) genes. (4) Conclusion: These findings highlight the clinical significance of E2F4as in predicting the prognosis of OC patients and suggest its potential in promoting tumour aggressiveness by the regulation of EMT-related mechanisms.

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“…Gene mutations confer cancer cells immortality and thus resistance to programmed cell death, thereby achieving the ability of unlimited proliferation [ 78 ]. We showed that metformin and olaparib could induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

Gralewska

Gajek

Marczak

et al. 2021

IJMS

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This study examined the effect of combination treatment with the poly (ADP-ribose) polymerase inhibitor olaparib and metformin on homologous recombination (HR)-proficient epithelial ovarian cancer (EOC). Ovarian cancer cell lines (OV-90 and SKOV-3) were treated with olaparib, metformin, or a combination of both. Cell viability was assessed by MTT and colony formation assays. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential were examined using the specific fluorescence probes, DCFH2-DA (2′,7′-dichloro-dihydrofluorescein diacetate) and JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine). Apoptotic and necrotic changes were measured by double staining with Hoechst 33258 and propidium iodide, orange acridine and ethidium bromide staining, phosphatidylserine externalization, TUNEL assay, caspase 3/7 activity, and cytochrome c and p53 expression. Compared with single-drug treatment, the combination of olaparib and metformin significantly inhibited cell proliferation and colony formation in HR-proficient ovarian cancer cells. ROS production preceded a decrease in mitochondrial membrane potential. The changes in ROS levels suggested their involvement in inducing apoptosis in response to combination treatment. The present results indicate a shift towards synergism in cells with mutant or null p53, treated with olaparib combined with metformin, providing a new approach to the treatment of gynecologic cancers. Taken together, the results support the use of metformin to sensitize EOC to olaparib therapy.

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Biguanides in combination with olaparib limits tumorigenesis of drug‐resistant ovarian cancer cells through inhibition of Snail

Cited by 13 publications

References 41 publications

Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

Long non-coding RNA HAL suppresses the migration and invasion of serous ovarian cancer by inhibiting EMT signaling pathway

Long Noncoding RNA E2F4as Promotes Progression and Predicts Patient Prognosis in Human Ovarian Cancer

Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

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