Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition

Abstract

The mitochondrial network is a major site of ATP production through the coupled integration of the electron transport chain (ETC) with oxidative phosphorylation. In melanoma arising from the V600E mutation in the kinase v-RAF murine sarcoma viral oncogene homolog B (BRAF), oncogenic signaling enhances glucose-dependent metabolism while reducing mitochondrial ATP production. Likewise, when BRAF is pharmacologically inhibited by targeted therapies ( PLX-4032/vemurafenib), glucose metabolism is reduced, and cells increase mitochondrial ATP production to sustain survival. Therefore, collateral inhibition of oncogenic signaling and mitochondrial respiration may help enhance the therapeutic benefit of targeted therapies. Honokiol (HKL) is a well tolerated small molecule that disrupts mitochondrial function; however, its underlying mechanisms and potential utility with targeted anticancer therapies remain unknown. Using wild-type BRAF and BRAF melanoma model systems, we demonstrate here that HKL administration rapidly reduces mitochondrial respiration by broadly inhibiting ETC complexes I, II, and V, resulting in decreased ATP levels. The subsequent energetic crisis induced two cellular responses involving cyclin-dependent kinases (CDKs). First, loss of CDK1-mediated phosphorylation of the mitochondrial division GTPase dynamin-related protein 1 promoted mitochondrial fusion, thus coupling mitochondrial energetic status and morphology. Second, HKL decreased CDK2 activity, leading to G cell cycle arrest. Importantly, although pharmacological inhibition of oncogenic MAPK signaling increased ETC activity, co-treatment with HKL ablated this response and vastly enhanced the rate of apoptosis. Collectively, these findings integrate HKL action with mitochondrial respiration and shape and substantiate a pro-survival role of mitochondrial function in melanoma cells after oncogenic MAPK inhibition.

Magnolol induces cell death through PI3K/Akt‐mediated epigenetic modifications boosting treatment of BRAF‐ and NRAS‐mutant melanoma

“…Another study demonstrated a potent antitumor effect of honokiol bis‐dichloroacetate in vemurafenib‐resistant melanoma in vivo . Consistently, a recent study showed a synergistic effect of honokiol and MAPK inhibitor in BRAFmt melanoma cells by disrupting mitochondrial electron transport chain . Since magnolol is structurally similar to honokiol, it is expected to have a similar effect on the BRAF inhibitor resistance melanoma cells; however, this requires further investigation.…”

Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors

“…We have shown that PEITC is able to resensitize to vemurafenib BRAFi-resistant melanoma cell lines confirming the important role of glutathione in their survival. But PEITC is also able to induce disruption of the mitochondrial electron transport complex I and to inhibit mitochondrial respiration in some cancer cells lines as leukemia cells 27 , thereby by this mechanism it could also increase cytotoxicity of BRAFi as seen with other complex I inhibitors metformin or phenformin 11 , 28 . To inhibit GSH metabolism, we have also used sulfasalazine, an xCT inhibitor; we found that this drug delay in vitro the growth of BRAFi-resistant melanoma.…”

Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure

“…Higher supplement of these redox proteins can potentially contribute to protective effect of MSCs, particularly enhancing the utilization of ROS in damaged tissues and protecting membrane integrity. It was shown that disintegration of respiratory chain or its functional deficiency play role in both, p53 and MAPK apoptosis signaling pathways [27,28].…”