How to make ovarian cancer cells “sick-too”

Miranda, Fabrizio; Ahmed, Ahmed A.

doi:10.1080/15384101.2016.1235846

Cited by 5 publications

(4 citation statements)

References 7 publications

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“…With regard to SIK2-targeted therapeutic strategies, Zhou et al recently reported the promising effects of the small-molecule SIK2 inhibitor in preclinical models of ovarian cancer [55]. These findings and others pave the way towards testing of SIK2 inhibitors in clinical trials [56].…”

Section: Orchestration Of the Metastatic Tumor Microenvironment In Thmentioning

confidence: 99%

An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment

et al. 2018

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Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.

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Section: Orchestration Of the Metastatic Tumor Microenvironment In Thmentioning

confidence: 99%

An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment

et al. 2018

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“…Although eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase (S6K1) are two main targets of mTORC1, we did not detect baseline S6K1 phosphorylation in MDA-MB-468 cells. We used phosphorylation of translational repressor 4E-BP1 as a marker of mTORC1 activity as it is generally accepted to reflect activation of mTORC1 29 and predict a response to AKT/mTOR inhibitors. 30 As shown in Figure 2A , aspirin and salicylic acid treatment attenuated the activity of mTORC1.…”

Section: Resultsmentioning

confidence: 99%

siRNA Knockdown of REDD1 Facilitates Aspirin-Mediated Dephosphorylation of mTORC1 Target 4E-BP1 in MDA-MB-468 Human Breast Cancer Cell Line

Savukaitytė

Gudoitytė

Bartnykaitė

et al. 2021

CMAR

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Background Mutations within genes encoding components of the PI3K/AKT/mTOR (phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin) signaling axis frequently activate the pathway in breast cancer, making it an attractive therapeutic target. Inhibition of mTORC1 (mechanistic target of rapamycin complex 1) activity upon aspirin treatment has been reported in breast cancer cells harboring PI3KCA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutation and is considered to account for anticancer action. Methods MDA-MB-468 (harbors mutated PTEN (phosphatase and TENsin homolog)), MCF-7 ( PI3KCA- mutated), MDA-MB-231 (no PI3K pathway mutations) cancer cell lines and MCF10A non-cancerous breast epithelial cells were employed for the assessment of modulation of mTORC1 signaling by aspirin. Targeted amplicon-based next-generation sequencing using the Ion Torrent technology was carried out to determine gene expression changes following drug treatment. Western blot was performed to analyze the expression and phosphorylation of proteins. Knockdown by siRNA approach was applied to assess the role of REDD1/DDIT4 (DNA damage-inducible transcript 4) in mTORC1 inhibition by aspirin. Results We show a decline in phosphorylation of mTORC1 downstream substrate 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1) in response to treatment with aspirin and its metabolite salicylic acid in MDA-MB-468, MCF-7, MDA-MB-231, and MCF10A cell lines. We further demonstrate a novel molecular response to aspirin in breast cancer cells. Specifically, we found that aspirin and salicylic acid increase the expression of REDD1 protein, that is known for its suppressive function towards mTORC1. Unexpectedly, we observed that siRNA knockdown of REDD1 expression facilitated aspirin-mediated suppression of mTORC1 downstream substrate 4E-BP1 phosphorylation in the MDA-MB-468 cell line. REDD1 downregulation slightly encouraged reduction in 4E-BP1 phosphorylation by aspirin in MCF-7 cells but did not elicit a reproducible effect in the MDA-MB-231 cell line. siRNA knockdown of REDD1 did not affect the expression of phosphorylated form of 4E-BP1 following aspirin treatment in MCF10A non-cancerous breast epithelial cells. Conclusion The current findings suggest that REDD1 downregulation might improve the anticancer activity of aspirin in a subset of breast tumors.

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“…For years, adipocytes are considered as energy producing and storing residents of fat tissue in the TME (Miranda and Ahmed, 2017 ). However, recent studies indicate that adipocytes may have other pathophysiological functions, and their interactions with cancer cells have been reported in breast, ovarian, colon, and gastric malignancies (Nieman et al, 2011 ).…”

Section: Ovary-associated Adipocytesmentioning

confidence: 99%

Revisiting ovarian cancer microenvironment: a friend or a foe?

Zhang

Chen

et al. 2017

Protein Cell

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Development of ovarian cancer involves the co-evolution of neoplastic cells together with the adjacent microenvironment. Steps of malignant progression including primary tumor outgrowth, therapeutic resistance, and distant metastasis are not determined solely by genetic alterations in ovarian cancer cells, but considerably shaped by the fitness advantage conferred by benign components in the ovarian stroma. As the dynamic cancer topography varies drastically during disease progression, heterologous cell types within the tumor microenvironment (TME) can actively determine the pathological track of ovarian cancer. Resembling many other solid tumor types, ovarian malignancy is nurtured by a TME whose dark side may have been overlooked, rather than overestimated. Further, harnessing breakthrough and targeting cures in human ovarian cancer requires insightful understanding of the merits and drawbacks of current treatment modalities, which mainly target transformed cells. Thus, designing novel and precise strategies that both eliminate cancer cells and manipulate the TME is increasingly recognized as a rational avenue to improve therapeutic outcome and prevent disease deterioration of ovarian cancer patients.

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How to make ovarian cancer cells “sick-too”

Cited by 5 publications

References 7 publications

An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment

An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment

siRNA Knockdown of REDD1 Facilitates Aspirin-Mediated Dephosphorylation of mTORC1 Target 4E-BP1 in MDA-MB-468 Human Breast Cancer Cell Line

Revisiting ovarian cancer microenvironment: a friend or a foe?

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