AMP-activated Protein Kinase Antagonizes Pro-apoptotic Extracellular Signal-regulated Kinase Activation by Inducing Dual-specificity Protein Phosphatases in Response to Glucose Deprivation in HCT116 Carcinoma

In-Ja Park,Wonchae Choe,Sung-Soo Kim,Insug Kang,Min-Jung Kim,Hee Yun,Joohun Ha

doi:10.1074/jbc.m109.085456

In-Ja Park, Wonchae Choe + Show 5 more

Open Access

https://doi.org/10.1074/jbc.m109.085456

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Abstract

Mitogen-activated protein kinase (MAPK) pathways are involved in the regulation of cellular responses, including cell proliferation, differentiation, cell growth, and apoptosis. Because these responses are tightly related to cellular energy level, AMP-activated protein kinase (AMPK), which plays an essential role in energy homeostasis, has emerged as another key regulator. In the present study, we demonstrate a novel signal network between AMPK and MAPK in HCT116 human colon carcinoma. Glucose deprivation activated AMPK and three MAPK subfamilies, extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK. Under these conditions, inhibition of endogenous AMPK by expressing a dominant-negative form significantly potentiated ERK activation, indicating that glucose deprivation-induced AMPK is specifically antagonizing ERK activity in HCT116 cells. Moreover, we provide novel evidence that AMPK activity is critical for p53-dependent expression of dual-specificity phosphatase (DUSP) 1 & 2, which are negative regulators of ERK. Notably, ERK exhibits pro-apoptotic effects in HCT116 cells under glucose deprivation. Collectively, our data suggest that AMPK protects HCT116 cancer cells from glucose deprivation, in part, via inducing DUSPs, which suppresses pro-apoptotic ERK, further implying that a signal network between AMPK and ERK is a critical regulatory point in coupling the energy status of the cell to the regulation of cell survival.

Highlights

AMPK activation through allosteric binding of AMP, which changes AMPK into a better substrate for phosphoactivation via an upstream kinase
Because these cellular responses are tightly related to the cellular energy level, a signal network between AMPK and Mitogen-activated protein kinase (MAPK) has emerged as a key regulatory point of significance
We demonstrate that AMPK induces the expression of dual-specificity phosphatase (DUSP) 1 & 2 via p53 activation under glucose deprivation, which leads to suppression of extracellular signal-regulated kinase (ERK) activity

Summary

Regulation of ERK by AMPK

ERK activity induced by IGF-1 [19], angiotensin II [20], or transaortic constriction [21], was down-regulated by AICAR. We examined the role of AMPK on the regulation of ERK in HCT116 human colon carcinoma under physiologically relevant conditions that activate both AMPK and ERK. As solid tumors outgrow the existing vasculature, they are continuously exposed to nutrient-depleted microenvironments, such as glucose deprivation, and must adapt to such environments for survival. We demonstrate that AMPK induces the expression of DUSP 1 & 2 via p53 activation under glucose deprivation, which leads to suppression of ERK activity. The glucose deprivation-induced ERK activity is pro-apoptotic. Our data suggest that AMPK protects HCT116 cancer cells from glucose deprivation, in part, via induction of DUSPs, which suppresses pro-apoptotic ERK

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