Polyunsaturated fatty acids induce ovarian cancer cell death through ROS-dependent MAP kinase activation

Tanaka, Aiko; Yamamoto, Akane; Murota, Kazuo; Tsujiuchi, Toshifumi; Iwamori, Masao; Fukushima, Nobuyuki

doi:10.1016/j.bbrc.2017.08.168

Cited by 42 publications

(24 citation statements)

References 23 publications

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“…ROS production is controlled by the mitochondria through a scavenging system and also affects the function of mitochondria, leading to MMP dysfunction and cell death . Polyunsaturated fatty acids can induce ovarian cancer cell death with a ROS‐dependent MAPK activation including c‐Jun N‐terminal kinase and P38 proteins . The present results echo prior findings that formononetin induced MMP disruption and P38 activation, leading to the death of ES2 and OV90 epithelial ovarian cancer cells.…”

Section: Discussionsupporting

confidence: 85%

The O‐methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation

Bazer

Lim

Song

2018

J of Cellular Biochemistry

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Formononetin is an isoflavone that is extracted from red clovers or soy. It has anti-oxidant, anti-proliferative, and anti-tumor effects against cells in various diseases. Several cohort studies have indicated that phytoestrogen intake, including formononetin, could reduce the risk of various carcinogenesis. In fact, many case-control studies have indicated the potential value of flavonoids as drug supplements in the treatment of many cancer patients. However, the toxic effects and the anti-cancer mechanism of formononetin in ovarian cancer are unknown. We investigated the toxicological mechanism of formononetin in ES2 and OV90 ovarian cancer cells. Formononetin suppressed cell proliferation through sub G0/G1 phase arrest and increased apoptosis in both cell lines. Furthermore, it induced loss of mitochondrial membrane potential and generation of reactive oxygen species in ES2 and OV90 cells. The formononetin-mediated regulation of cell proliferation and apoptosis involved decreased phosphorylation of ERK1/2, P90RSK, AKT, P70S6K, and S6 proteins, and increased phosphorylation of P38 protein in ES2 and OV90 cells. Co-treatment of formononetin with pharmacological inhibitors (LY294002 or U0126) revealed additional anti-proliferative effects on the two human ovarian cancer cell types. Conclusively, the results indicate the potential value of formononetin as an anti-cancer agent in human ovarian cancer.

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Section: Discussionsupporting

confidence: 85%

The O‐methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation

Bazer

Lim

Song

2018

J of Cellular Biochemistry

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“…Thus, it is tempting to speculate that increase in PUFA levels during DR maybe activating p38-MAPK pathway and associated CyTP genes by increasing sensitivity of TRP channels. PUFAs can also activate p38-MAPK through the generation of ROS, and supplementation of Vitamin E is able to abrogate this response 59 . However, activation through ROS seems counter intuitive, because DR reduces the level of these molecules.…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction

et al. 2020

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The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of “Xenobiotic Detoxification Program” (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.

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“…Epidemiological and clinical studies have suggested that polyunsaturated fatty acids (PUFAs) could have health benefits and therapeutic effects in cancer treatment. A recent study demonstrated that ω-3 and ω-6 PUFAs could induce cell death in ovarian cancer cell lines through ROS-dependent MAP kinase activation [ 72 ]. Moreover, Li et al [ 73 ] showed that ovarian CSCs identified as ALDH + /CD133 + population have higher levels of unsaturated fatty acids (UFAs) and stearoyl-CoA desaturase-1 (SCD1, an enzyme produces mono-UFAs) compared to non-CSCs (ALDH − /CD133 − ).…”

Section: Ovarian Cancer Metabolismmentioning

confidence: 99%

Chemoresistance in ovarian cancer: exploiting cancer stem cell metabolism

Wong

2018

J Gynecol Oncol

122

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Ovarian cancer is most deadly gynecologic malignancies worldwide. Chemotherapy is the mainstay treatment for ovarian cancer. Despite the initial response is promising, frequent recurrence in patients with advanced diseases remains a therapeutic challenge. Thus, understanding the biology of chemoresistance is of great importance to overcome this challenge and will conceivably benefit the survival of ovarian cancer patients. Although mechanisms underlying the development of chemoresistance are still ambiguous, accumulating evidence has supported an integral role of cancer stem cells (CSCs) in recurrence following chemotherapy. Recently, tumor metabolism has gained interest as a reason of chemoresistance in tumors and chemotherapeutic drugs in combination with metabolism targeting approaches has been found promising in overcoming therapeutic resistance. In this review, we will summarize recent studies on CSCs and metabolism in ovarian cancer and discuss possible role of CSCs metabolism in chemoresistance.

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Polyunsaturated fatty acids induce ovarian cancer cell death through ROS-dependent MAP kinase activation

Cited by 42 publications

References 23 publications

The O‐methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation

The O‐methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation

Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction

Chemoresistance in ovarian cancer: exploiting cancer stem cell metabolism

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