Cytochrome c and cancer cell metabolism: A new perspective

Abstract

Cytochrome c is a vital electron carrier in the mitochondrial respiratory chain. When the outer membrane of mitochondria becomes permeable, cytochrome c is discharged into the cytoplasm, where it initiates the intrinsic apoptosis pathway. The complex interaction between cytochrome c and apoptosis protease-activating factor-1 (Apaf-1) leads to the formation of the apoptosome and activation of a cascade of caspases, highlighting the critical role of cytochrome c in controlling cell death mechanisms. Additionally, cytochrome c undergoes post-translational modifications, especially phosphorylation, which intricately regulate its roles in both respiration and apoptosis. These modifications add layers of complexity to how cytochrome c effectively controls cellular functions. cytochrome c becomes a lighthouse in the intricate web of cancer, its expression patterns providing hints about prognosis and paths toward treatment. Reduced levels of cytochrome c have been observed in cancer tissues, indicating a potential inhibition of apoptosis. For instance, in glioma tissues, cytochrome c levels were lower compared to healthy tissues, and this reduction became more pronounced in advanced stages of the disease. However, the role of cytochrome c in cancer becomes more intricate as it becomes intertwined with the metabolic reprogramming of cancer cells. This suggests that cytochrome c plays a crucial role in tumor progression and resistance to treatment. Viewing cytochrome c as a molecular mosaic reveals that it is not merely a protein, but also a central player in determining cellular fate. This realization opens up exciting avenues for potential advancements in cancer diagnosis and treatment strategies. Despite the advancements made, the narrative surrounding cytochrome c remains incomplete, urging further exploration into its complexities and the biological implications linked to cancer. cytochrome c stands as a beacon of hope and a promising target for therapy in the battle against cancer, particularly due to its significant involvement in tumor metabolism. It holds the potential for a future where innovative solutions can be developed to address the intricate challenges of cellular fate. In this review, we have endeavored to illuminate the multifaceted domain of cytochrome c drawing connections among apoptosis, metabolic reprogramming, and the Warburg effect in the context of cancer.

Keywords: And cancer; Apoptosis; Apoptosome; Cancer; Cytochrome c; Oxidative phosphorylation; Warburg effect.

Graphical abstract

Fig. 1

Role of cytochrome C in apoptosis. Numerous death signals gather at the mitochondria, releasing a variety of intermembrane space proteins. Numerous apoptotic stimuli, such as death domain receptors, chemotherapy, agents that damage DNA, withdrawal of growth factors, and radiation, cause mitochondria to become activated. This leads to the release of apoptotic proteins, such as endonuclease G, cytochrome c, AIF, Smac/DIABLO, and Omi/HtrA2. Cytochrome C binds to Apaf-1 to cause caspase activation. IAP inhibition of caspases can be counteracted by Omi/HtrA2 and Smac/DIABLO.

Fig. 2

The release of cytochrome c from mitochondria and its subsequent downstream processes. When cytochrome c is released from mitochondria, it triggers a cascade of events leading to apoptosis, or programmed cell death. This release is tightly regulated and can be influenced by various factors including cellular stress, mitochondrial dynamics, and apoptotic signaling pathways.

Fig. 3

The diagram illustrates the metabolic reprogramming observed in cancer cells, highlighting key alterations such as increased glutamine metabolism, enhanced glycolysis with lactate fermentation, perturbations in the tricarboxylic acid (TCA) cycle, utilization of intermediates from the pentose phosphate pathway, and the synthesis of lipids, amino acids, and nucleotides utilizing TCA cycle intermediates.

Fig. 4

In the presence of oxygen, tumors and other highly proliferative cells preferentially convert most of their glucose into lactate through a process known as the Warburg Effect. Despite yielding approximately 4 molecules of ATP per molecule of glucose, this pathway provides cancer cells with a significant growth advantage over oxidative phosphorylation (OXPhos) due to its faster chemical reaction. In normally differentiated tissues, glucose undergoes conversion to pyruvate when oxygen is available. Pyruvate then enters oxidative phosphorylation (OXPhos), generating approximately 36 molecules of ATP per molecule of glucose. Alternatively, when glucose oxidation does not occur, lactate is produced, yielding about 2 molecules of ATP per molecule of glucose.

Fig. 5

The bioinformatic analysis of Cyt C using online portals. (A) Timer Analysis showing the expression pattern of Cytochrome c in various cancers which reveals that Cytochrome c expression is highly upregulated in several cancers including breast cancer. (B) Gepia-2 Analysis further validates that Cytochrome c is dysregulated in several malignancies including Breast Cancer.

Fig. 6

Bioinformatic survival analysis using KM plotter database. A) Overall survival of breast cancer patients. The survival probability increases with decrease in the level of cytochrome c and vice versa. B) The Relapse Free Survival of breast cancer patients. High mRNA expression of Cytochrome c is associated with worse RFS, with a hazard ratio reaching up to 1.74 in breast cancer.