Oleic acid induces migration through a FFAR1/4, EGFR and AKT-dependent pathway in breast cancer cells

Marcial-Medina, Cleofas; Ordoñez-Moreno, Alejandra; González-Reyes, Christian; Cortés‐Reynosa, Pedro; Salazar, Eduardo Pérez

doi:10.1530/ec-18-0543

Cited by 34 publications

(26 citation statements)

References 67 publications

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“…Notably, this was also observed for the highly invasive ACHN cells, which are derived from pleural effusion metastasis. Earlier studies have shown that activating AKT inhibition can suppress cell migration (Marcial-Medina et al, 2019; Mete et al, 2019). Our own results indicated that nobiletin inhibits AKT activation, suggesting that this could be one of the mechanisms underlying the inhibitory effect of nobiletin on the invasion and migration of renal carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells

et al. 2019

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Nobiletin is a polymethoxy flavonoid isolated from Citrus depressa and Citrus reticulata. It has been reported that nobiletin can suppress tumors. We primarily explored the antitumor effects of nobiletin and the associated potential mechanisms in ACHN and Caki-2 renal carcinoma cells. A CCK-8 assay and cloning experiments were used to assess cell viability, and a transwell assay and scratch test were used to assess metastatic ability. The cell cycle was analyzed by flow cytometry, whereas apoptosis was analyzed using flow cytometry and a terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay. Protein expression was examined by Western blot and immunofluorescence. Renal cancer cells were subcutaneously transplanted into nude mice for in vivo studies. The data showed that nobiletin administration significantly dose-and time-dependently suppressed renal cancer cell proliferation; moreover, nobiletin treatment induced cell cycle arrest in the G0/G1 phase and promoted apoptosis. Immunofluorescence analysis indicated that nobiletin decreased the nuclear localization of signal transducer and activator of transcription 3 (STAT3) and YY1-associated protein 1 (YY1AP1). Western blot showed that the levels of phosphorylated SRC, phosphorylated AKT serine/threonine kinase (AKT), and phosphorylated STAT3 were decreased, whereas that of phosphorylated YY1AP1 was increased. The results further showed that application of insulin-like growth factor 1 (IGF1) was able to reverse the nobiletin-induced changes in the levels of phosphorylated AKT, phosphorylated STAT3, and phosphorylated YY1AP1, and could also reverse the antitumor effects of nobiletin. The results of in vivo experiments showed that, compared to the control, tumor volume and weight were both reduced following nobiletin treatment. In conclusion, our study demonstrated that nobiletin can inhibit renal carcinoma cell viability and provides a novel therapeutic approach for the treatment of kidney cancer.

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Section: Discussionmentioning

confidence: 99%

Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells

et al. 2019

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“…A couple of studies confirmed the pro-migratory role of AKT2 [151, 157, 164–166] and dealt with possible mechanisms behind the crucial role of AKT2 in breast cancer migration, invasion and metastasis. AKT2, but not AKT1 or AKT3, enhances an integrin β1-mediated attachment to and an invasion through collagen IV and to a minor degree through laminin in vitro and in vivo.…”

Section: Akt Isoform Specificity In Breast Cancer: Migration and Invamentioning

confidence: 99%

Distinct functions of AKT isoforms in breast cancer: a comprehensive review

2019

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Background: AKT, also known as protein kinase B, is a key element of the PI3K/AKT signaling pathway. Moreover, AKT regulates the hallmarks of cancer, e.g. tumor growth, survival and invasiveness of tumor cells. After AKT was discovered in the early 1990s, further studies revealed that there are three different AKT isoforms, namely AKT1, AKT2 and AKT3. Despite their high similarity of 80%, the distinct AKT isoforms exert non-redundant, partly even opposing effects under physiological and pathological conditions. Breast cancer as the most common cancer entity in women, frequently shows alterations of the PI3K/AKT signaling. Main content: A plethora of studies addressed the impact of AKT isoforms on tumor growth, metastasis and angiogenesis of breast cancer as well as on therapy response and overall survival in patients. Therefore, this review aimed to give a comprehensive overview about the isoform-specific effects of AKT in breast cancer and to summarize known downstream and upstream mechanisms. Taking account of conflicting findings among the studies, the majority of the studies reported a tumor initiating role of AKT1, whereas AKT2 is mainly responsible for tumor progression and metastasis. In detail, AKT1 increases cell proliferation through cell cycle proteins like p21, p27 and cyclin D1 and impairs apoptosis e.g. via p53. On the downside AKT1 decreases migration of breast cancer cells, for instance by regulating TSC2, palladin and EMT-proteins. However, AKT2 promotes migration and invasion most notably through regulation of β-integrins, EMT-proteins and F-actin. Whilst AKT3 is associated with a negative ER-status, findings about the role of AKT3 in regulation of the key properties of breast cancer are sparse. Accordingly, AKT1 is mutated and AKT2 is amplified in some cases of breast cancer and AKT isoforms are associated with overall survival and therapy response in an isoform-specific manner. Conclusions: Although there are several discussed hypotheses how isoform specificity is achieved, the mechanisms behind the isoform-specific effects remain mostly unrevealed. As a consequence, further effort is necessary to achieve deeper insights into an isoform-specific AKT signaling in breast cancer and the mechanism behind it.

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“…Long-chain (n-6) fatty acids (linoleic acid) are well-known as pro-inflammatory factors, which induce the development of breast cancer [47], whereas other fatty acids reversely impact on the breast cancer patients [43,45,49]. FFAs induce breast cancer invasion by activating the epidermal growth factor receptor, GTP-binding protein, and protein kinase C pathway [57], and by controlling cell proliferation via phosphatidylinositol 3-kinase (PI3K) [58] and cell migration through free fatty acid receptor 1 and 4 and AKT pathway activation [59]. In vitro, David et al stimulated breast cancer cells proliferation by supplement of FFAs on serum-free medium in a dose-dependent manner, linoleic acid can stimulate breast cancer cell growth at three times higher concentration than oleic acid (0.75 µg/mL) [47].…”

Section: Adipocytes Regulate Breast Cancer Via Their Metabolic Submentioning

confidence: 99%

The Effects of Adipocytes on the Regulation of Breast Cancer in the Tumor Microenvironment: An Update

Chu

Phuong

Tien

et al. 2019

Cells

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Obesity is a global pandemic and it is well evident that obesity is associated with the development of many disorders including many cancer types. Breast cancer is one of that associated with a high mortality rate. Adipocytes, a major cellular component in adipose tissue, are dysfunctional during obesity and also known to promote breast cancer development both in vitro and in vivo. Dysfunctional adipocytes can release metabolic substrates, adipokines, and cytokines, which promote proliferation, progression, invasion, and migration of breast cancer cells. The secretion of adipocytes can alter gene expression profile, induce inflammation and hypoxia, as well as inhibit apoptosis. It is known that excessive free fatty acids, cholesterol, triglycerides, hormones, leptin, interleukins, and chemokines upregulate breast cancer development. Interestingly, adiponectin is the only adipokine that has anti-tumor properties. Moreover, adipocytes are also related to chemotherapeutic resistance, resulting in the poorer outcome of treatment and advanced stages in breast cancer. Evaluation of the adipocyte secretion levels in the circulation can be useful for prognosis and evaluation of the effectiveness of cancer therapy in the patients. Therefore, understanding about functions of adipocytes as well as obesity in breast cancer may reveal novel targets that support the development of new anti-tumor therapy. In this systemic review, we summarize and update the effects of secreted factors by adipocytes on the regulation of breast cancer in the tumor microenvironment.

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Oleic acid induces migration through a FFAR1/4, EGFR and AKT-dependent pathway in breast cancer cells

Cited by 34 publications

References 67 publications

Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells

Nobiletin Inhibits Cell Viability via the SRC/AKT/STAT3/YY1AP1 Pathway in Human Renal Carcinoma Cells

Distinct functions of AKT isoforms in breast cancer: a comprehensive review

The Effects of Adipocytes on the Regulation of Breast Cancer in the Tumor Microenvironment: An Update

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