The Double-Edged Sword of SIRT3 in Cancer and Its Therapeutic Applications

Abstract

Reprogramming of cellular energy metabolism is considered an emerging feature of cancer. Mitochondrial metabolism plays a crucial role in cancer cell proliferation, survival, and metastasis. As a major mitochondrial NAD+-dependent deacetylase, sirtuin3 (SIRT3) deacetylates and regulates the enzymes involved in regulating mitochondrial energy metabolism, including fatty acid oxidation, the Krebs cycle, and the respiratory chain to maintain metabolic homeostasis. In this article, we review the multiple roles of SIRT3 in various cancers, and systematically summarize the recent advances in the discovery of its activators and inhibitors. The roles of SIRT3 vary in different cancers and have cell- and tumor-type specificity. SIRT3 plays a unique function by mediating interactions between mitochondria and intracellular signaling. The critical functions of SIRT3 have renewed interest in the development of small molecule modulators that regulate its activity. Delineation of the underlying mechanism of SIRT3 as a critical regulator of cell metabolism and further characterization of the mitochondrial substrates of SIRT3 will deepen our understanding of the role of SIRT3 in tumorigenesis and progression and may provide novel therapeutic strategies for cancer targeting SIRT3.

Honokiol, an inducer of sirtuin‐3, protects against non‐steroidal anti‐inflammatory drug‐induced gastric mucosal mitochondrial pathology, apoptosis and inflammatory tissue injury

“…Indeed, a recent report suggests that honokiol is apparently safe for human consumption as a natural antioxidant supplement (Sarrica et al, 2018). Further, it is also worth mentioning that several studies on cancers have projected Sirt3 as a double‐edged sword, reflecting its cancer and/or context‐specific oncogenic or tumour‐suppressive attributes, depending on the nature and metabolic requirements of the tumours and their unique microenvironment (Ouyang et al, 2022). However, in regard to non‐malignant pathologies, Sirt3 stimulation is mostly beneficial and offers protection against a range of pathologies associated with inflammation, oxidative stress, mitochondrial dysfunction and energy dyshomeostasis (Bugga et al, 2022; Dikalova et al, 2020; Zhang et al, 2020).…”

Mitochondrial Sirtuins in Cancer: A Revisited Review from Molecular Mechanisms to Therapeutic Strategies

“…Primarily located within the mitochondria, SIRT3 is a NAD + -dependent deacetylase, which means it relies on nicotinamide adenine dinucleotide to remove acetyl groups from various protein substrates. This activity is essential for the regulation of metabolic processes, including fatty acid oxidation, the tricarboxylic acid (TCA) cycle, and the electron transport chain 33 , 47 . Functionally, SIRT3 has been shown to deacetylate and activate numerous enzymes critical for mitochondrial metabolism 33 .…”

“…SIRT3 also modulates the activity of complex I of the electron transport chain, thereby influencing ATP production and reducing ROS levels. By deacetylating isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase 2 (SOD2), SIRT3 boosts antioxidant defenses and reduces oxidative damage 47 . The role of SIRT3 extends beyond metabolism to include aging and cellular stress responses.…”

Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy

“…Cancer cells use mitochondrial‐derived strong antioxidant machinery, thereby suppressing ROS levels, among which sirtuin‐3(SIRT3) is considered a key molecule 42 . SIRT3 affects mitochondrial metabolism, including TCA, urea cycle, amino acid metabolism, fatty acid oxidation, ETC/OXPHOS ROS detoxification, mitochondrial dynamics, and the mitochondrial unfolded protein response (UPR) 43 .…”

“…41 Cancer cells use mitochondrial-derived strong antioxidant machinery, thereby suppressing ROS levels, among which sirtuin-3 (SIRT3) is considered a key molecule. 42 SIRT3 affects mitochondrial metabolism, including TCA, urea cycle, amino acid metabolism, fatty acid oxidation, ETC/OXPHOS ROS detoxification, mitochondrial dynamics, and the mitochondrial unfolded protein response (UPR). 43 Studies have exhibited that silencing of SIRT3 is along with decreasing mitochondrial function, and oxygen consumption, which suggests an appealing strategy to render colorectal cancer cells more sensitive to treatment.…”