Adiponectin Represses Colon Cancer Cell Proliferation via AdipoR1- and -R2-Mediated AMPK Activation

Abstract

In obesity, dysregulation of adipocytokines is involved in several pathological conditions including diabetes and certain cancers. As a member of the adipocytokines, adiponectin plays crucial roles in whole-body energy homeostasis. Recently, it has been reported that the level of plasma adiponectin is reduced in several types of cancer patients. However, it is largely unknown whether and how adiponectin affects colon cancer cell growth. Here, we show that adiponectin suppresses the proliferation of colon cancer cells including HCT116, HT29, and LoVo. In colon cancer cells, adiponectin attenuated cell cycle progression at the G(1)/S boundary and concurrently increased expression of cyclin-dependent kinase inhibitors such as p21 and p27. Adiponectin stimulated AMP-activated protein kinase (AMPK) phosphorylation whereas inhibition of AMPK activity blunted the effect of adiponectin on the proliferation of colon cancer cells. Furthermore, knockdown of adiponectin receptors such as AdipoR1 and AdipoR2 relieved the suppressive effect of adiponectin on the growth of colon cancer cells. In addition, adiponectin repressed the expression of sterol regulatory element binding protein-1c, which is a key lipogenic transcription factor associated with colon cancers. These results suggest that adiponectin could inhibit the growth of colon cancer cells through stimulating AMPK activity.

Salutary effects of adiponectin on colon cancer: in vivo and in vitro studies in mice

“…Also, it has been shown that adiponectin mediates expression of cell cycle regulatory proteins and activates AMPK signalling in colon cancer cell lines 41. Similar to these reports, we observed that the suppressive effect of adiponectin on colon cancer cell proliferation was mediated by activation of AMPK and/or decreasing phosphorylation of S6.…”

Obesity Biomarkers, Metabolism and Risk of Cancer: An Epidemiological Perspective

“…Adiponectin plays an important role in energy metabolism and has insulin-sensitizing and anti-inflammatory properties [53,8]. In addition, anti-neoplastic properties such as inhibition of proliferation and promotion of apoptosis have been observed to be upregulated by adiponectin in cancer cells [54]. High adiponectin concentrations have been suggested to play a protective role in the development of cancer either directly through inhibition of cell growth and induction of apoptosis or indirectly through improved insulin sensitivity and reduced inflammation [54].…”

“…In addition, anti-neoplastic properties such as inhibition of proliferation and promotion of apoptosis have been observed to be upregulated by adiponectin in cancer cells [54]. High adiponectin concentrations have been suggested to play a protective role in the development of cancer either directly through inhibition of cell growth and induction of apoptosis or indirectly through improved insulin sensitivity and reduced inflammation [54]. Epidemiological evidence for an association between pre-diagnostic adiponectin concentrations and obesity-associated cancer has emerged from several investigations.…”

Mechanisms linking obesity and cancer

“…Adiponectin negatively influences growth of most obesity-related cancer types, such as prostate [157] and colon [158] cancers. A study on breast cancer also proved a negative effect of adiponectin on migration [159].…”