Research ArticleCell Biology

IKK promotes cytokine-induced and cancer-associated AMPK activity and attenuates phenformin-induced cell death in LKB1-deficient cells

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Science Signaling  10 Jul 2018:
Vol. 11, Issue 538, eaan5850
DOI: 10.1126/scisignal.aan5850

An inflammatory way to activate AMPK

In its best-known function as a sensor of energy status, the kinase AMPK is activated by phosphorylation mediated by the tumor suppressor LKB1. Antonia and Baldwin characterized a different pathway for AMPK activation involving TAK1, a kinase associated with inflammatory pathways. They found that this process required phosphorylation of AMPK by the TAK1 target IKK and that it occurred independently of LKB1 and, in certain cell lines, independently of TAK1 as well, indicating that TAK1-independent pathways that activate IKK could also stimulate AMPK. Combining an IKK inhibitor with the cancer drug phenformin improved its ability to kill LKB1-deficient cancer cells, highlighting a new potential treatment for cancers lacking this tumor suppressor.


The 5′ AMP-activated protein kinase (AMPK) is an energy sensor that is activated upon phosphorylation of Thr172 in its activation loop by the kinase LKB1, CAMKK2, or TAK1. TAK1-dependent AMPK phosphorylation of Thr172 is less well characterized than phosphorylation of this site by LKB1 or CAMKK2. An important target of TAK1 is IκB kinase (IKK), which controls the activation of the transcription factor NF-κB. We tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172. IKK was required for the phosphorylation of Thr172 in AMPK in response to treatment with the inflammatory cytokine IL-1β or TNF-α or upon TAK1 overexpression. In addition, IKK regulated basal AMPK Thr172 phosphorylation in several cancer cell types independently of TAK1, indicating that other modes of IKK activation could stimulate AMPK. We found that IKK directly phosphorylated AMPK at Thr172 independently of the tumor suppressor LKB1 or energy stress. Accordingly, in LKB1-deficient cells, IKK inhibition reduced AMPK Thr172 phosphorylation in response to the mitochondrial inhibitor phenformin. This response led to enhanced apoptosis and suggests that IKK inhibition in combination with phenformin could be used clinically to treat patients with LKB1-deficient cancers.

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