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Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma - PubMed

  • ️Sat Jan 01 2022

Review

Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma

Hong Toan Lai et al. Front Cell Dev Biol. 2022.

Abstract

Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades no improvement of prognosis was achieved. It is therefore crucial to identify new drug candidates for OS treatment to combat drug resistance, limit relapse, and stop metastatic spread. Two acquired hallmarks of cancer cells, mitochondria-related regulated cell death (RCD) and metabolism are intimately connected. Both have been shown to be dysregulated in OS, making them attractive targets for novel treatment. Promising OS treatment strategies focus on promoting RCD by targeting key molecular actors in metabolic reprogramming. The exact interplay in OS, however, has not been systematically analyzed. We therefore review these aspects by synthesizing current knowledge in apoptosis, ferroptosis, necroptosis, pyroptosis, and autophagy in OS. Additionally, we outline an overview of mitochondrial function and metabolic profiles in different preclinical OS models. Finally, we discuss the mechanism of action of two novel molecule combinations currently investigated in active clinical trials: metformin and the combination of ADI-PEG20, Docetaxel and Gemcitabine.

Keywords: ADI-PEG20; Metformin; metabolic reprogramming; mitochondria; osteosarcoma; regulated cell death.

Copyright © 2022 Lai, Naumova, Marchais, Gaspar, Geoerger and Brenner.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

Molecular mechanisms of apoptosis.

FIGURE 2
FIGURE 2

Molecular mechanisms of ferroptosis. Ferroptosis is characterized by oxidation of lipids upon inhibition of SLC7A11/SLC3A2 (Xc- system) transport complex or GPX4 activity. The reaction involved ROS and Fe2+. Ferroptosis is initiated by inhibition of the SLC7A11/SLC3A2 (Xc- system) transport complex or GPX4 activity. ROS and Fe2+ directly catalyze lipid peroxides to form damaging free radicals via the Fenton reaction. The SLC7A11/SLC3A2 antiporter is responsible for GSL biosynthesis by importing cystine into cytosol. GPX4 inhibits ferroptosis by transforming lipid peroxides into lipid alcohols.

FIGURE 3
FIGURE 3

Molecular mechanisms of necroptosis. The scheme presents the three signaling pathways downstream of TNFR involving complex I, complex IIa and complex IIb formation. These complexes influence differentially cell fate. In the absence of caspase 8, necroptosis is then induced.

FIGURE 4
FIGURE 4

Molecular mechanisms of pyroptosis. Upon the initiation of noncanonical pyroptosis or canonical pyroptosis, different inflammatory actors are triggered. On the left side, pro-caspase 4/5 are cleaved for their maturation and participate in noncanocical pathway to cleave GSDMD into its active form N-GSDMD. On the right side, canonical pathway requires inflammasome formation to activate the caspase-1. The caspase-1 is necessary for GSDMD cleavage and IL-1β and IL-18 maturation, release and final steps of cell swelling and lysis.

FIGURE 5
FIGURE 5

Molecular mechanisms of autophagy. The various steps of autophagy process are depicted following mTORC1 regulation by p53, AMPK and MAPK/ERK signaling. Autophagy is activated by the initiation complex ULK1/Atg1 and PIK3/Beclin-1 complex, which enables the autophagosome formation. The elongation and maturation depend on two ubiquitin-like conjugation systems (Atg12/Atg5/Atg6 system and Atg8/PE system). Many signaling pathways are involved in the regulation of autophagy. Due to the activation of p53 signaling or AMPK, activity of the mTORC1 complex is decreased and triggers autophagy activation. On the other hand, the activation of PI3K/Akt and MAPK/Erk pathways induce the increase of mTORC1 activity that results in the inhibition of autophagy.

FIGURE 6
FIGURE 6

Mechanisms of action of metformin. Metformin targets mitochondrial complex I of respiratory chain, thus induces the activation of AMPK signalling pathway, resulting in the inhibition of glucogenesis and lipogenesis. The overactivation of AMPK pathway also inhibits the mTORC1 pathways, thus, protein synthesis.

FIGURE 7
FIGURE 7

Mechanisms of action of ADI-PEG20 combined with Docetaxel and Gemcitabine in Ongoing Clinical for ASS1-deficient cancer (adapted from Prudner et al., 2019). Shown on the left are the synergic molecular mechanism of ADI-PEG20, Docetaxel, and Gemcitabine in ASS1-deficient OS. Together with Docetaxel, the arginine starvation induced by ADI-PEG20 induces c-Myc translocation. c-Myc acts as a transcription factor that stimulates the expression of the hENT1 gene which is important for Gemcitabine uptake to inhibit DNA synthesis in OS. Shown on the right are the metabolic impacts in arginine auxotrophic conditions, where the loss of arginine inhibits the activity of glycolysis-mediated enzyme PKM2, resulting in decrease of aerobic glycolysis. Moreover, in ASS1-deficient breast cancer, ADI-PEG20 treatment inhibits the mitochondrial activities, resulting in the inhibition of mitochondrial respiratory complexes. While in melanoma and sarcoma, arginine starvation causes the increase of extracellular glutamine uptake with higher expression of glutaminolysis-related actors, resulting in the metabolic reprogramming for the consumption of glutamine as a fuel source via TCA cycle, and OXPHOS. This metabolic profile represents the reduced Warburg effect.

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