Cells Lacking the Fumarase Tumor Suppressor Are Protected from Apoptosis through a Hypoxia-Inducible Factor-Independent, AMPK-Dependent Mechanism

Abstract

g Loss-of-function mutations of the tumor suppressor gene encoding fumarase (FH) occur in individuals with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). We found that loss of FH activity conferred protection from apoptosis in normal human renal cells and fibroblasts. In FH-defective cells, both hypoxia-inducible factor 1␣ (HIF-1␣) and HIF-2␣ accumulated, but they were not required for apoptosis protection. Conversely, AMP-activated protein kinase (AMPK) was activated and required, as evidenced by the finding that FH inactivation failed to protect AMPK-null mouse embryo fibroblasts (MEFs) and AMPK-depleted human renal cells. Activated AMPK was detected in renal cysts, which occur in mice with kidney-targeted deletion of Fh1 and in kidney cancers of HLRCC patients. In Fh1-null MEFs, AMPK activation was sustained by fumarate accumulation and not by defective energy metabolism. Addition of fumarate and succinate to kidney cells led to extracellular signal-regulated kinase 1/2 (ERK1/2) and AMPK activation, probably through a receptor-mediated mechanism. These findings reveal a new mechanism of tumorigenesis due to FH loss and an unexpected pro-oncogenic role for AMPK that is important in considering AMPK reactivation as a therapeutic strategy against cancer.

Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK

“…In line with the above idea, genetic studies showed a procancer role of AMPK in the in vivo growth of H-RAS-transformed fibroblasts and astrocytic tumors, in pancreatic cancer, and in a subtype of renal cell carcinoma (28)(29)(30)(31). Additional genetic studies also underscore the requirement of AMPK in cancer cell metabolic programming (32,33); cell division (34)(35)(36)(37); migration (38), protection against stress; and anticancer therapy (39)(40)(41).…”

“…Because LKB1, the kinase that activates AMPK is a tumor suppressor, AMPK activation by agonists is perceived to have therapeutic benefits. This belief remains despite the puzzling observation that in contrast to canonical tumor suppressors, LKB1 is required for cellular transformation (1) and LKB1-or AMPK-deficient cancer cells can be sensitive to chemotherapeutic agents (27,31,57). Ironically, these agents include the very AMPK agonists that are used to activate AMPK.…”

AMPK: A Contextual Oncogene or Tumor Suppressor?

“…the Warburg effect , a widespread phenotype of cancer cells. Interestingly AMPK is required for apoptotic resistance conferred by FH deficiency(66). AMPK regulates glycolysis by phosphorylating and activating PFKFB3, one of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1~4), as shown in monocytes(67).…”

Metabolic control of signalling pathways and metabolic auto‐regulation

“…Therefore, any change in cellular metabolism resulting in altered AMP concentration and/or AMP:ATP ratio might modulate AMPK activity (Hardie et al., ; Shirwany and Zou ) (Figure ). Examples for energy stress induction and consequently AMPK activating events include the inhibition of complex I of the electron transport chain (Hinke et al., ; Ota et al., ), inhibition of fumarate hydratase (Tong et al., 2011; Bardella et al., ) or more unexpected metabolic alterations such as serine starvation (Maddocks et al., ).…”