Targeting Mitochondria in Melanoma.

Sepideh Aminzadeh-Gohari,Luca Catalano,Barbara Kofler,Daniela D. Weber,René G. Feichtinger,Roland Lang

doi:10.3390/biom10101395

Sepideh Aminzadeh-Gohari, Luca Catalano + Show 4 more

Open Access

https://doi.org/10.3390/biom10101395

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Journal: Biomolecules	Publication Date: Sep 30, 2020
Citations: 30	License type: CC BY 4.0

Affiliation: Paracelsus Medical University

Abstract

Drastically elevated glycolytic activity is a prominent metabolic feature of cancer cells. Until recently it was thought that tumor cells shift their entire energy production from oxidative phosphorylation (OXPHOS) to glycolysis. However, new evidence indicates that many cancer cells still have functional OXPHOS, despite their increased reliance on glycolysis. Growing pre-clinical and clinical evidence suggests that targeting mitochondrial metabolism has anti-cancer effects. Here, we analyzed mitochondrial respiration and the amount and activity of OXPHOS complexes in four melanoma cell lines and normal human dermal fibroblasts (HDFs) by Seahorse real-time cell metabolic analysis, immunoblotting, and spectrophotometry. We also tested three clinically approved antibiotics, one anti-parasitic drug (pyrvinium pamoate), and a novel anti-cancer agent (ONC212) for effects on mitochondrial respiration and proliferation of melanoma cells and HDFs. We found that three of the four melanoma cell lines have elevated glycolysis as well as OXPHOS, but contain dysfunctional mitochondria. The antibiotics produced different effects on the melanoma cells and HDFs. The anti-parasitic drug strongly inhibited respiration and proliferation of both the melanoma cells and HDFs. ONC212 reduced respiration in melanoma cells and HDFs, and inhibited the proliferation of melanoma cells. Our findings highlight ONC212 as a promising drug for targeting mitochondrial respiration in cancer.

Highlights

Accounting for ~4% of cancers in adolescents, cutaneous melanoma has become a common malignancy owing to its dramatic rise among fair-skinned people [1]
To gain insight into the levels of oxidative phosphorylation (OXPHOS) and glycolysis in melanoma cells, we initially evaluated the levels of OXPHOS complexes and voltage-dependent anion-selective channel 1 (VDAC1) in four melanoma cell lines with mutations affecting BRAF or NRAS or neither oncogene—BRAF and NRAS wild-type (WM3311), BRAF-mutated (WM47 and A375), and NRAS-mutated (WM3000)—and compared them to human dermal fibroblasts (HDFs) as non-cancerous skin cells
Based on Western blot analysis, the expression of VDAC1 and OXPHOS complexes was generally higher in the melanoma cell lines WM3311, WM47, and A375 compared to WM3000 and HDFs (Figure 1a–g)

Summary

Introduction

Accounting for ~4% of cancers in adolescents, cutaneous melanoma has become a common malignancy owing to its dramatic rise among fair-skinned people [1]. The prognosis of patients with melanoma was very poor once metastatic disease had developed. Approval in 2011 of the BRAF-inhibitor vemurafenib and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-antibody ipilimumab has resulted in significant improvements in the treatment of advanced melanoma. The introduction of anti–PD-1–based therapies, either in combination with ipilimumab or as single agents, has further improved the overall survival of patients with metastatic melanoma (reviewed in [3]). Despite the effectiveness of these treatments, approximately half of advanced melanoma patients still die from their disease, underlining the urgent need for additional therapeutic strategies

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