Targeting breast cancer metabolism with a novel inhibitor of mitochondrial ATP synthesis

Abstract

Inhibitors of mitochondrial respiration and ATP synthesis may promote the selective killing of respiration-competent cancer cells that are critical for tumor progression. We previously reported that CADD522, a small molecule inhibitor of the RUNX2 transcription factor, has potential for breast cancer treatment. In the current study, we show that CADD522 inhibits mitochondrial oxidative phosphorylation by decreasing the mitochondrial oxygen consumption rate (OCR) and ATP production in human breast cancer cells in a RUNX2-independent manner. The enzyme activity of mitochondrial ATP synthase was inhibited by CADD522 treatment. Importantly, results from cellular thermal shift assays that detect drug-induced protein stabilization revealed that CADD522 interacts with both α and β subunits of the F1-ATP synthase complex. Differential scanning fluorimetry also demonstrated interaction of α subunits of the F1-ATP synthase to CADD522. These results suggest that CADD522 might target the enzymatic F1 subunits in the ATP synthase complex. CADD522 increased the levels of intracellular reactive oxygen species (ROS), which was prevented by MitoQ, a mitochondria-targeted antioxidant, suggesting that cancer cells exposed to CADD522 may elevate ROS from mitochondria. CADD522-increased mitochondrial ROS levels were enhanced by exogenously added pro-oxidants such as hydrogen peroxide or tert-butyl hydroperoxide. Conversely, CADD522-mediated cell growth inhibition was blocked by N-acetyl-l-cysteine, a general ROS scavenger. Therefore, CADD522 may exert its antitumor activity by increasing mitochondrial driven cellular ROS levels. Collectively, our data suggest in vitro proof-ofconcept that supports inhibition of mitochondrial ATP synthase and ROS generation as contributors to the effectiveness of CADD522 in suppression of tumor growth.

Targeting mitochondrial metabolism for metastatic cancer therapy

“…Therefore, inhibition of these pathways may restrict tumor cell proliferation or promote cell death through feedback inhibition of respiratory capacity, increased ROS, and lower glucose utilization. Our recent published data 34–36 support the hypothesis that mitochondrial OxPhos and elevation of ROS are important drivers of oncogenesis. Partial inhibition of MAPK (ERK1/2) signaling or targeting mitochondrial ATP generation via ATP synthase targeting can disrupt the redox balance in tumor cells.…”

Targeting of Ubiquitin E3 Ligase RNF5 as a Novel Therapeutic Strategy in Neuroectodermal Tumors

“…Since oxidative stress is often associated to cell death induction, we evaluated the effect of 10 μM Analog-1 on apoptosis of NB and melanoma cell lines by immunofluorescence [ 36 ]. Figure 5 b shows that both SH-SY5Y and MZ2-MEL cells presented a significant increase in the percentage of apoptotic cells in a time- and dose-dependent manner.…”

“…ATP-synthase is a central enzyme of the cellular energy metabolism, which is highly expressed during cancer growth and linked to a poor prognosis in almost all tumors [ 32 , 52 , 53 , 54 , 55 ]. Targeting ATP-synthase has been proposed as a promising approach for cancer therapy [ 33 , 36 ]. However, several challenges in translating preclinical ATP synthase targeting drugs to the clinic mainly remain due to their unacceptable in vivo toxicity [ 56 ].…”

Cross-talks in colon cancer between RAGE/AGEs axis and inflammation/immunotherapy

“…WE as the main characteristics of cancer can thus be triggered by infectious agents, followed by consequent effects such as genomic mutations [ 15 ], possibly switching benign adenomas to malignant carcinomas in the case of colorectal cancers. Inhibitors for mitochondrial ATP synthesis are being developed for colon cancer [ 16 ] in which the uptake of glucose is overregulated [ 17 ]. Moreover, tumor suppressor protein p53 was demonstrated negatively influences the oncogenic metabolic adaptation of cancer cells reverting WE [ 18 ].…”