Ovarian cancer (OC) is a life-threatening malignancy that represents 3.6% female malignancies worldwide (1). It currently ranks as the seventh most common type of gynecological cancer and 20th as the most common type of cancer worldwide. OC has the highest mortality of all gynecologic malignancies (1,2). According to a recent report, it was estimated that there were 295,414 new cases of OC diagnosed in 2018 and 184,799 cases of mortality resulting from this disease worldwide (3). Tumor debulking surgery followed by platinum and paclitaxel chemotherapy is currently the standard clinical treatment of OC (4). However, the survival rate of patients with advanced OC remains at ~30%, with the primary reasons being late discovery and chemoresistance. In particular, chemoresistance is mediated by both the tumor microenvironment and inherent resistance of OC cells to chemotherapy (5). Therefore, enhancement of responses to current treatment and the development of novel therapeutic strategies are urgently required to improve the survival rate.

Autophagy is a protective, catabolic process that operates to maintain intracellular homeostasis by recycling organelles and macromolecules (6). During this process, defective or aged organelles and other cytoplasmic components are enclosed by double-membrane vesicles to form autophagosomes. This then fuses with a lysosome where the vesicular contents are degraded into amino acids, lipids and carbohydrates by the lysosomal enzymes. The degradation products are in turn recycled to make new proteins and organelles (7). A basal level of autophagy is in operation under physiological conditions (8). However, downregulation or upregulation of autophagy induced by stress factors, including alterations in the levels of growth factors, hypoxia and cytotoxic damage, can result in cell death or cell adaptation in response (9). Autophagy also appears to serve contradictory roles in the development of cancer. Evidence exists reporting that inhibition of genes associated with autophagy can promote tumor development, whereas the expression of proteins associated with autophagy has also been demonstrated to result in inhibitory effects in several types of cancers (10–14). Therefore, autophagy can exert antitumor effects, but in contrast cancer cells may survive cellular stress in adverse microenvironments by utilizing autophagy, thereby promoting the development of tumors (15). In addition, autophagy is somewhat considered to be a double-edged sword in the clinical field of cancer. Promotion of autophagy can induce cell death, in a manner that is similar to apoptosis, whilst protective cellular autophagy has also been reported to be the major underlying cause of therapy resistance among cancer cells. Therefore, increasing the sensitivity of cancer cells to anticancer therapy by inhibiting autophagy remains a viable option (16).

Sirtuins are nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylases that are highly conserved among eukaryotic organisms, of which seven isoforms exist in mammals (17–19). They serve important roles in a number of biological and pathological processes. In particular, Sirt3 is localized to mitochondria, where it modulates the production of reactive oxygen species (ROS) to limit oxidative damage in cellular components (20). A wide range of important biological activities have been documented to be controlled by Sirt3, including the regulation of nuclear gene expression, metabolism, neuroprotection, cardiovascular disease, cancer cell cycle progression, and cell proliferation and apoptosis (21–24). Previously, the role of Sirt3 as a hallmark of cancer has been attracting significant research attention (25). Metabolism is an important caveat to cancer development (26), such that ATP is required for the maintenance of intracellular metabolic activity (27). A number of metabolic processes have been revealed to be regulated by Sirt3, including fatty-acid oxidation and oxidative phosphorylation (28,29). These observations suggested that Sirt3 could be a key regulator of cancer physiology.

Currently, there are a number of studies on autophagy and Sirt3 in cardiovascular diseases, neuronal diseases and hepatotoxicity (30–32). However, almost no article has conducted research on the relationship between autophagy, OC and Sirt3. Therefore, the present review primarily discussed the potential relationship between Sirt3 and autophagy in OC, with the aim to provide a possible novel direction for OC research and therapeutic strategies.

OC poses a significant threat to the health of women worldwide, and is a disease in which Sirt3 has been reported serve a regulatory role. Of note, this disease is gradually becoming the leading cause of mortality associated with gynecological cancer worldwide in both developing and developed countries (1). Several reports have suggested that OC is regulated by Sirt3 using a multitude of mechanisms, which is summarized in this section.

In a previous study, it was found that muscle tissues after exercise exhibit elevated expression levels of the Sirt3 protein, which gave rise to the hypothesis that the expression of Sirt3 is regulated by energy metabolism (33). Energy metabolism is also associated with the regulation of tumor growth and metastasis. Sirt3 is regarded as a tumor suppressor, due to a previous finding that its expression is reduced in tumors (34,35). The activation of cellular autophagy and apoptosis was demonstrated to be controlled by Sirt3 via the regulation of several signaling pathways during the development of OC. A previous study found that expression of the Sirt3 protein was significantly downregulated in OC tissues and in highly metastatic HO-8910PM cell lines (35,36). In addition, Xiang et al (37) demonstrated that the activation of Sirt3 exerted a proapoptotic function in SKOV3 cells. These findings suggested that overexpression of Sirt3 can induce OC cell death. In terms of mitochondrial dynamics, a previous study revealed that stabilization of Sirt3 can increase mitochondrial biogenesis and cristae remodeling in OC tissues (38). Additionally, stabilization of optic atrophy protein 1, which increased resistance to apoptosis, was demonstrated to be regulated by increasing the expression of Sirt3 and prohibitin 2 (38). Activation of Sirt3 has also been found to enhance the sensitivity of OC cells to cisplatin (39), rendering Sirt3 to be a novel therapeutic target. In addition, Sirt3 was reported to be a favorable independent prognostic factor for overall survival for patients with serious OC in a previous study (40). In conclusion, Sirt3 serves an important role in the development of OC, with therapeutic and prognostic implications.

Autophagy is a catabolic process that serves to maintain intracellular homeostasis by recycling damaged cellular organelles (41), which has been studied since the 1960s (42). Over the past decades, the molecular mechanisms underlying this process have been revealed gradually. It has been suggested that autophagy is a common phenomenon that occurs during both physiological and pathological conditions. According to the sizes of the substrates involved and degradation rate, autophagy can be divided into three sub-categories: i) Macro-autophagy; ii) microautophagy; and iii) chaperone-mediated autophagy (43). Although different types of autophagy utilize distinct mechanisms to degrade lysosomal proteins, common underlying characteristics remain (44). The autophagy pathway consists of the following six steps: i) Initiation of autophagy; ii) biogenesis of the phagophore; iii) expansion of the phagophore; iv) formation of the autophagosome; v) fusion with the lysosome; and vi) reformation of the lysosome (45). Autophagy is constitutively active at low levels in all cell types under physiological conditions, but can be potentiated by nutrient deprivation, hypoxia, endoplasmic reticulum stress, pathogenic toxicity and immune injury, to maintain intracellular homeostasis (46). Previous studies have demonstrated that autophagy serves an important role in the pathological processes of various diseases, including neurodegenerative and cardiovascular disease, cancer, infectious diseases and immune deficiency (47–50). Autophagy has been described as a double-edged sword, since it can exert both tumor suppression and growth promotion (51). In this section, the mechanism of autophagy in OC is discussed in detail.

OC ranks as the most lethal gynecological malignancy, with high morbidity and mortality. Autophagy serves an important role in OC through the expression of autophagy-associated proteins, including beclin-1, microtubule-associated proteins 1A/1B light chain 3B (LC3) and p53. Beclin-1 is a tumor suppressor, which is an important checkpoint protein that is involved in autophagy and tumor cell apoptosis (52,53). It has been reported to mediate various functions in tumors, where its expression level varies depending on the type of malignancy. A previous study revealed that the expression level of beclin-1 was higher in ovarian epithelial cancers, which can be used as an independent risk factor for the prognosis of patients with this disease (54). In addition, other proteins linked to autophagy can mediate functions in OC, which are in turn associated with a number of signaling pathways, including the PI3K/AKT/mTOR and p53 signaling pathway. These are summarized in this section.

Sirt3 belongs to the NAD⁺-dependent protein deacetylase family and is responsible for the majority of mitochondrial protein deacetylation (74). It has been reported to serve an important role in almost every aspect of mitochondrial biology, such as mitochondrial biogenesis and mitochondrial oxidative stress (30,75–77). Although Sirt3 is located in mitochondria, almost every major key component of autophagy is cytosolic. Therefore, a type of communication mechanism must exist between mitochondria and cytosol during the regulation of Sirt3 activity and autophagy. In previous years, accumulating evidence has suggested that there are a series of signaling pathways between Sirt3 and autophagy, including the p62, PI3K/AKT, AMPK-mTOR pathway and the mitochondrial ROS-superoxide dismutase 2 (SOD2) pathway. This section aimed to summarize the known information on its mechanism (Fig. 1).

Autophagy is a fundamental catabolic process that has been reported to be involved in the progression of a variety of diseases. It can serve a protective role in OC cells from cell death since it may enhance resistance to cisplatin (105). A previous investigation revealed that cisplatin treatment activated autophagy, whereas Bcl-2-associated athanogene 3 attenuated cisplatin resistance by inhibiting autophagy (106). However, recent studies have also suggested that autophagy can inhibit the growth of OC, since it has been found to promote OVCAR-3 cell death (107). By contrast, findings from another previous study suggested that inhibition of autophagy promoted the proliferation and invasion of OC cells via the PI3K/AKT/mTOR pathway (108). These findings demonstrated that autophagy is a double-edged sword in the regulation of OC physiology. Sirt3 serves an important role in the maintenance of intracellular homeostasis in OC. Previous studies have indicated that there is a close mutual regulatory relationship between Sirt3 and autophagy, which are linked by the aforementioned signaling pathways in the present review. Metformin-induced overexpression of Sirt3 promoted apoptosis and mitochondrial dysfunction whilst increasing the activation of AMPK in OC cell lines (109). In addition, metformin has been documented to promote autophagy in OC (110). S1, a novel Bcl-2 inhibitor, has also been reported to exert autophagic effects in OC by interrupting the interaction between Bcl-2 and beclin1 in OC to promote apoptosis (111); however, high doses and longer exposure of S1 can overpower the protective function of autophagy and induce apoptosis (112,113). Yang et al (114) previously found that S1 promoted JNK3 expression, thus increasing cell sensitivity to apoptosis. Sirt3 can also regulate autophagy via the glutathione S-transferase P/JNK/autophagy pathway, such that Sirt3 knockdown has been demonstrated to alleviate S1-induced apoptosis (Fig. 2) (37).

Autophagy serves an important role in recycling damaged organelles and maintaining intracellular homeostasis. Sirt3 is a potential therapeutic target, since it has been previously reported to activate autophagy. In the present review, although the potential relationship between Sirt3 and autophagy in OC was explored, there remains an insufficient number of studies on this topic. The associated underlying mechanism in the Sirt3-induced autophagic process in OC remains unclear. With further study, novel insights into the molecular relationship between Sirt3 and autophagy may contribute to the development of novel therapeutic interventions for OC.