Leptin activates Akt in oesophageal cancer cells via multiple atorvastatin-sensitive small GTPases

Beales, Ian; Ogunwobi, Olorunseun O.

doi:10.1007/s11010-021-04067-8

Cited by 6 publications

(6 citation statements)

References 56 publications

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“…Obesity and serum leptin are also a strong risk factors for Barrett’s esophagus [ 122 ], a precursor lesion in esophageal carcinoma [ 123 ]. Leptin and Ob-R expression has been found to play carcinogenic roles [ 124 ], since its binding activates the Akt signaling pathway in esophageal cancer cells via multiple atorvastatin sensitive small GTPases, leading to the growth and antiapoptosis of cancer cells [ 125 ]. Tumor leptin expression has also been related with chemotherapy resistance in gastro-esophageal adenocarcinomas, suggesting that leptin expression is potentially useful as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-esophageal adenocarcinoma [ 126 ].…”

Section: Role Of Leptin As a Bad Actor In Cancermentioning

confidence: 99%

Leptin, Both Bad and Good Actor in Cancer

Jiménez‐Cortegana¹,

López-Saavedra²,

Sánchez-Jiménez³

et al. 2021

Biomolecules

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Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the “obesity paradox”, and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology.

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Section: Role Of Leptin As a Bad Actor In Cancermentioning

confidence: 99%

Leptin, Both Bad and Good Actor in Cancer

Jiménez‐Cortegana¹,

López-Saavedra²,

Sánchez-Jiménez³

et al. 2021

Biomolecules

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“…Moreover, leptin is known to induce AKT activation in various cell types. [33][34][35] However, in SV40 cells, leptin did not elicit AKT phosphorylation (Figure 3F).…”

Section: Leptin Induces Mmp-1 Expression In Sv40 Cellsmentioning

confidence: 90%

Leptin Induces MMP-1 Expression Through the RhoA/ERK1/2/NF-κB Axis in Human Intervertebral Disc Cartilage Endplate-Derived Stem Cells

Hua,

Li,

et al. 2023

JIR

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Intervertebral disc (IVD) degeneration, associated with aging, may cause low back pain and disability, with obesity as a significant risk factor. In a prior study, we found a positive correlation between IVD degeneration and levels of matrix metalloproteinase-1 (MMP-1) and leptin. Yet, the interaction between MMP-1 and leptin in IVD degeneration is unclear. Our research seeks to explore leptin's influence on MMP-1 expression and the underlying mechanisms in human intervertebral disc cartilage endplatederived stem cells, specifically SV40 cells. Methods: The mRNA and protein expression in leptin-stimulated SV40 cells were assessed using RT-real-time PCR and Western blotting or ELISA, respectively. We examined leptin-mediated RhoA activation through a GTP-bound RhoA pull-down assay. Furthermore, the phosphorylation levels of mitogen-activated protein kinases and AKT in leptin-stimulated SV40 cells were analyzed using Western blotting. The activation of NF-κB by leptin was investigated by assessing phosphorylation of IKKα/β, IκBα, and NF-κB p65, along with the nuclear translocation of NF-κB p65. To understand the underlying mechanism behind leptin-mediated MMP-1 expression, we employed specific inhibitors. Results: Leptin triggered the mRNA and protein expression of MMP-1 in SV40 cells. In-depth mechanistic investigations uncovered that leptin heightened RhoA activity, promoted ERK1/2 phosphorylation, and increased NF-κB activity. However, leptin did not induce phosphorylation of JNK1/2, p38, or AKT. When we inhibited RhoA, ERK1/2, and NF-κB, it resulted in a decrease in MMP-1 expression. Conversely, inhibition of reactive oxygen species and NADPH oxidase did not yield the same outcome. Additionally, inhibiting RhoA or ERK1/2 led to a reduction in leptin-induced NF-κB activation. Moreover, inhibiting RhoA also decreased leptin-mediated ERK1/2 phosphorylation. Conclusion: These results indicated that leptin induced MMP-1 expression in SV40 cells through the RhoA/ERK1/2/NF-κB axis. This study provided the pathogenic role of leptin and suggested the potential therapeutic target for IVD degeneration.

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“…Atorvastatin reduced leptin-induced Akt signaling in OE33 cells, presenting a viable option for leptin modulation and cancer interception [81] (Figure 2). The preclinical development of adiponectin-analogs [82,83] and leptin-receptor antagonists [84] is underway; however, more research is required before they can be put to clinical use.…”

Section: Metabolic Pathwaysmentioning

confidence: 99%

Translating Molecular Biology Discoveries to Develop Targeted Cancer Interception in Barrett’s Esophagus

Samaddar

Buckles

Saha

et al. 2023

IJMS

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Esophageal adenocarcinoma (EAC) is a rapidly increasing lethal tumor. It commonly arises from a metaplastic segment known as Barrett’s esophagus (BE), which delineates the at-risk population. Ample research has elucidated the pathogenesis of BE and its progression from metaplasia to invasive carcinoma; and multiple molecular pathways have been implicated in this process, presenting several points of cancer interception. Here, we explore the mechanisms of action of various agents, including proton pump inhibitors, non-steroidal anti-inflammatory drugs, metformin, and statins, and explain their roles in cancer interception. Data from the recent AspECT trial are discussed to determine how viable a multipronged approach to cancer chemoprevention would be. Further, novel concepts, such as the repurposing of chemotherapeutic drugs like dasatinib and the prevention of post-ablation BE recurrence using itraconazole, are discussed.

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Leptin activates Akt in oesophageal cancer cells via multiple atorvastatin-sensitive small GTPases

Cited by 6 publications

References 56 publications

Leptin, Both Bad and Good Actor in Cancer

Leptin, Both Bad and Good Actor in Cancer

Leptin Induces MMP-1 Expression Through the RhoA/ERK1/2/NF-κB Axis in Human Intervertebral Disc Cartilage Endplate-Derived Stem Cells

Translating Molecular Biology Discoveries to Develop Targeted Cancer Interception in Barrett’s Esophagus

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