LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective

Abstract

Inactivating mutations of the tumor suppressor gene Liver Kinase B1 (LKB1) are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.

Restoration of RNA helicase DDX5 suppresses hepatitis B virus (HBV) biosynthesis and Wnt signaling in HBV-related hepatocellular carcinoma

“…In addition to DDX5 (Figure 1 ) , the increased expression of these miRNAs also downregulates other known cellular targets, including PTEN 22 and LKB1 34 . Indeed, HBV replicating cells display reduced PTEN and LKB1 levels, which regulate AKT phosphorylation ( Figure S2 B) , and AMPK activity 35 , respectively. Importantly both of these pathways are known to exert a positive effect on HBV replication 36 - 38 .…”

Cell Signaling and Translational Developmental Therapeutics

“… 117 , 118 , 119 The AMPK is itself regulated by phosphorylation, with the most notable regulators being Liver kinase B1 (LKB1) and ataxia-telangiectasia mutated (ATM). 120 , 121 , 122 , 123 , 124 , 125 LKB1 is often mutated in tumor cells, leading to dysregulation of energy sensing and autophagy regulation. In the nucleus ATM senses DNA damage and cytosolic ATM senses the levels of reactive oxygen species; ATM at both cellular locations phosphorylates and activates the AMPK.…”

The Remedial Potential of Lycopene in Pancreatitis through Regulation of Autophagy

“…The enzyme AMPK (5'-AMP-activated protein kinase) is the main sensor of cellular ATP levels. Activated by liver kinase B1 (LKB1) in response to a decreased ATP/AMP ratio, AMPK phosphorylates and activates the tuberous sclerosis 1/2 (TSC1/2) complex, resulting in the inhibition of the mTORC1 activator, Rheb [59]. AMPK can also promote autophagy induction by activating p27 kip1 [60].…”