Multiple signal pathways in obesity-associated cancer

Abstract

Obesity is increasing worldwide and reaches to a large proportion of the population in developed countries. Thus, obesity-associated cancer has become a major health problem. Multiple cancer risk factors in obesity have been identified including insulin/insulin-like growth factor axis, adipokines and cytokines; and multiple intracellular signal pathways have been studied. However, the role of each signal pathway in obesity-associated cancer is controversial. In this review, the recent studies on signal pathways in obesity-associated cancer are summarized and a unified explanation is provided. Multiple risk factors could initially activate phosphoinositide 3-kinase (PI3K/Akt), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) pathways. With increased severity of obesity, mammalian target of rapamycin (mTOR), which is down-stream of both PI3K/Akt and MAPK, is highly activated. Activated mTOR in turn inhibits the PI3K/Akt pathway and further activates the STAT3 pathway. This may explain the activation of the PI3K/Akt pathway at the early stage of obesity and its inhibition at the later stage. mTOR inhibition may be used for cancer therapy, but it may be necessary to be combined with the PI3K/Akt inhibitor as decreased mTOR activity will release its feedback inhibition on the PI3K/Akt pathway, which is under the influence of multiple cancer risk factors in obesity. Thus, dual inhibitors of PI3K and mTOR may provide a novel approach.

Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis

“…APN has beneficial effects by decreasing the levels of many risk factors, it stimulates apoptosis and controls proliferation, adhesion, invasion, and colony formation and regulates various signalling pathways such as AMPK and Jak/STAT (Chen, 2011,Ungefroren et al, 2015Kim et al, 2016). On the other hand, elevated levels of leptin are discussed as a factor driving cancer development and progression, because leptin is known to be mitogenic, proinflammatory, antiapoptotic, and proangiogenic (Ungefroren et al, 2015).…”

“…APN and leptin are two highly expressed adipokines that have opposing effects. APN has predominantly anti-inflammatory effects and has decreased blood levels of APN in obesity, whereas leptin has multiple proinflammatory effects and its blood levels are increased in obesity Chen, 2011). APN inhibits IL-6 secretion and lowers the levels of TNF-a (Chen, 2011;Ungefroren et al, 2015) and leptin stimulates production of IL-6 and TNF-a .…”

“…IL-6 and TNF-a blood levels are also increased in obesity . Furthermore, increased cancer incidence and poor prognosis are associated with increased blood levels of IL-6, TNF-a and leptin; and decreased blood levels of APN (Chen, 2011). (Fig.…”

“…For example, increased lipid mobilization and energy expenditure is favourable in obesity, while it is deleterious in cancer (Petruzzelli and Wagner, 2016). Even obesity and cachexia are opposite states, their relationship to cancer is not exactly antagonistic as there is an extensive overlap in the signalling pathways and molecular components involved (Tsoli and Robertson, 2013;Chen, 2011;Ungefroren et al, 2015). One such group of metabolic components are the FAs, which likely play a crucial role in the pathogenesis of both health conditions and cancer (Tsoli and Robertson, 2013;Chen, 2011;Ungefroren et al, 2015).…”

Obesidad y cáncer: la tormenta perfecta

“…La concentración de IGF-1 es más alta en hombres que en mujeres lo que puede explicar las diferencias de género descritas para el CCR 21,22 .…”