Oncotarget

Research Papers:

Glucagon promotes colon cancer cell growth via regulating AMPK and MAPK pathways

Takashi Yagi, Eiji Kubota _, Hiroyuki Koyama, Tomohiro Tanaka, Hiromi Kataoka, Kenro Imaeda and Takashi Joh

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Oncotarget. 2018; 9:10650-10664. https://doi.org/10.18632/oncotarget.24367

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Abstract

Takashi Yagi1, Eiji Kubota1, Hiroyuki Koyama1, Tomohiro Tanaka1, Hiromi Kataoka1, Kenro Imaeda1 and Takashi Joh1

1Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan

Correspondence to:

Eiji Kubota, email: ekubota@med.nagoya-cu.ac.jp

Keywords: glucagon; colon cancer; proliferation; incretin; glucagon signalling

Received: July 20, 2017    Accepted: January 19, 2018    Published: January 31, 2018

ABSTRACT

Cancer is one of the major causes of death in diabetic patients, and an association between antidiabetic drugs and cancer risk has been reported. Such evidence implies a strong connection between diabetes and cancer. Recently, glucagon has been recognized as a pivotal factor implicated in the pathophysiology of diabetes. Glucagon acts through binding to its receptor, glucagon receptor (GCGR), and cross-talk between GCGR-mediated signals and signaling pathways that regulate cancer cell fate has been unveiled. In the current study, expression of GCGR in colon cancer cell lines and colon cancer tissue obtained from patients was demonstrated. Glucagon significantly promoted colon cancer cell growth, and GCGR knockdown with small interfering RNA attenuated the proliferation-promoting effect of glucagon on colon cancer cells. Molecular assays showed that glucagon acted as an activator of cancer cell growth through deactivation of AMPK and activation of MAPK in a GCGR-dependent manner. Moreover, a stable GCGR knockdown mouse colon cancer cell line, CMT93, grew significantly slower than control in a syngeneic mouse model of type 2 diabetes with glycemia and hyperglucagonemia. The present observations provide experimental evidence that hyperglucagonemia in type 2 diabetes promotes colon cancer progression via GCGR-mediated regulation of AMPK and MAPK pathways.


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