Mitochondrial uncoupler exerts a synthetic lethal effect against β‐catenin mutant tumor cells

Abstract

The wingless/int‐1 (Wnt) signal transduction pathway plays a central role in cell proliferation, survival, differentiation and apoptosis. When β‐catenin: a component of the Wnt pathway, is mutated into an active form, cell growth signaling is hyperactive and drives oncogenesis. As β‐catenin is mutated in a wide variety of tumors, including up to 10% of all sporadic colon carcinomas and 20% of hepatocellular carcinomas, it has been considered a promising target for therapeutic interventions. Therefore, we screened an in‐house natural product library for compounds that exhibited synthetic lethality towards β‐catenin mutations and isolated nonactin, an antibiotic mitochondrial uncoupler, as a hit compound. Nonactin, as well as other mitochondrial uncouplers, induced apoptosis selectively in β‐catenin mutated tumor cells. Significant tumor regression was observed in the β‐catenin mutant HCT 116 xenograft model, but not in the β‐catenin wild type A375 xenograft model, in response to daily administration of nonactin in vivo. Furthermore, we found that expression of an active mutant form of β‐catenin induced a decrease in the glycolysis rate. Taken together, our results demonstrate that tumor cells with mutated β‐catenin depend on mitochondrial oxidative phosphorylation for survival. Therefore, they undergo apoptosis in response to mitochondrial dysfunction following the addition of mitochondrial uncouplers, such as nonactin. These results suggest that targeting mitochondria is a potential chemotherapeutic strategy for tumor cells that harbor β‐catenin mutations.

Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

“…All of the drugs used reduced Wnt signaling in these tumor cells already at sublethal concentrations ( Figure S4B) and within 8 h after application ( Figures 2G, 2I, and S4C). In these cells, the effects of XAV939 and the other compounds were less pronounced on the b-catenin level compared to HEK293 cells (Li et al, 2015), most likely due to a mutation in the b-catenin itself in HCT116 (Ichimanda et al, 2018;Shikata et al, 2017). Similar results were obtained in another colon cancer line, DLD1, characterized by constitutively active Wnt signaling due to a truncation in adenomatous polyposis coli (APC) (Homfray et al, 1998;Kishida et al, 1998), concerning viability upon treatment ( Figure S4D), reduction of Wnt signaling (Figures S4E and S4G), ATP depletion ( Figure S4F), and endoplasmic reticulum stress ( Figure S4G).…”

Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis

“…In this scenario, the direct mitochondrial modulation of Wnt signaling is a new frontier in oncology [ 73 ]. Indeed, mitochondrial uncouplers, like nonactin (a member of a family of naturally occurring cyclic ionophores known as macrotetrolide antibiotics), have been shown to selectively kill mutant β-catenin-harboring tumor cells in vivo in xenograft mouse models [ 112 ]. Furthermore, pyrvinium pamoate, an FDA-approved drug that inhibits NADH-fumarate reductase systems leading to electron transport chain and ATP synthesis decrease [ 113 ], was demonstrated to block Wnt/β-catenin signaling by selectively potentiating casein kinase 1α (CK1α) in colorectal cancer cells harboring APC mutation and aberrant Wnt activation [ 114 ].…”

Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth

“…It is well known that Wnt and mitochondrial function are both critical for cancer growth and metastasis. Mitochondria in cancer cells are often compromised, and a growing body of literature demonstrates uncoupling mitochondrial oxidative phosphorylation can overcome resistance to anticancer drugs 45–50 . Thus, the multifunctional activity of DK419 may have additional benefits in the treatment of cancer.…”