Obesity, the PI3K/Akt signal pathway and colon cancer

Abstract

Obesity is currently reaching epidemic levels worldwide and is a major predisposing factor for a variety of life-threatening diseases including diabetes, hypertension and cardiovascular diseases. Recently, it has also been suggested to be linked with cancer. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5-2 fold with obesity-associated colon cancer accounting for 14-35% of total incidence. Several factors, altered in obesity, may be important in cancer development including increased levels of blood insulin, insulin-like growth factor I, leptin, TNF-alpha, IL-6 as well as decreased adiponectin. A unifying characteristic of all these factors is that they increase the activity of the PI3K/Akt signal pathway. The PI3K/Akt signal pathway in turn activates signals for cell survival, cell growth and cell cycle leading to carcinogenesis. Here we review the evidence that PI3K/Akt and its downstream targets are important in obesity-associated colon cancer and thus, that targeted inhibition of this pathway could be employed for the prevention of obesity-associated colon cancer and incorporated into the therapy regime for those with irremovable colon cancers.

Aloe-emodin from rhubarb (Rheum rhabarbarum) inhibits lipopolysaccharide-induced inflammatory responses in RAW264.7 macrophages

“…For instance, Akt can phosphorylate IκB, leading to NF-κB release and activation (Huang and Chen, 2009). The MAPK pathways, which are extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 MAPK pathways in particular (Herlaar and Brown, 1999), also regulate the synthesis of inflammation mediators at the level of transcription and translation through activation of NF-κB and AP-1 transcription factors (Kaminska, 2005).…”

The Src/PI3K/Akt signal pathway may play a key role in decreased drug efficacy in obesity‐associated cancer

“…The Src/PI3K/Akt pathway is highly activated by multiple cancer risk factors which are elevated in obesity [Jaffe and Schwartz, 2008;Huang and Chen, 2009b]. These factors include increased blood levels of insulin, IGF-1, leptin, TNF-alpha, and IL-6.…”

“…These factors include increased blood levels of insulin, IGF-1, leptin, TNF-alpha, and IL-6. These factors have been demonstrated to activate Src/PI3K/Akt to promote carcinogenesis [Jaffe and Schwartz, 2008;Roberts et al, 2009;Huang and Chen, 2009b]. In addition, decreased blood level of adiponectin in obesity also contributes to the action of the pathway as adiponectin can block insulin and leptin [Fujisawa et al, 2008;Huang and Chen, 2009a].…”

“…The increased cancer incidence in obesity is accounted for by the activation of cellular signal pathways which are carcinogenic such as Src/PI3K/Akt pathway [Chen, 2008;Huang and Chen, 2009b]. However, the mechanism for the poor prognosis in obesity-associated cancer is still unclear.…”

The IL-23/IL-17 axis may be important in obesity-associated cancer by way of the activation of multiple signal pathways

“…They include increased blood levels of insulin, insulin-like growth factor 1, leptin, tumor necrosis factor a and interleukin (IL)-6, and decreased blood level of adiponectin. 2 These altered factors activate several cellular signal pathways that promote cancer formation and poor prognosis. 2 I read with great interest the paper 'Increased activity of interleukin-23/interleukin-17 proinflammatory axis in obese women' published in the November issue of the International Journal of Obesity.…”