ONCOLOGY REPORTS 42: 1647-1655, 2019 Autophagy modulation in bladder cancer development and treatment (Review) FAPING LI, HUI GUO, YUXUAN YANG, MINGLIANG FENG, BIN LIU, XIANG REN and HONGLAN ZHOU Department of Urology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China Received April 24, 2019; Accepted August 1, 2019 DOI: 10.3892/or.2019.7286 Abstract. Bladder cancer (BC) is a potentially life-threatening 1. Introduction malignancy. Due to a high recurrence rate, frequent surveil- lance strategies and intravesical drug therapies, BC is Bladder cancer (BC) is a potentially life-threatening malig- considered one of the most expensive tumors to treat. As a nancy that is considered one of the most expensive tumors fundamental evolutionary catabolic process, autophagy plays in terms of treatment and medical care (1-3). After prostate an important role in the maintenance of cellular environ- cancer, it is the second most common type of urological cancer mental homeostasis by degrading and recycling damaged and ranks 10th among the most common types of cancer cytoplasmic components, including macromolecules and around the globe (4). It has been estimated that there were organelles. Scientific studies in the last two decades have 549,393 new cases of BC and 199,922 deaths resulting from shown that autophagy acts as a double‑edged sword with this disease worldwide in 2018, according to a report from regard to the treatment of cancer. On one hand, autophagy the International Agency for Research on Cancer (4). The inhibition is able to increase the sensitivity of cancer cells to primary histological subtype of human BC is transitional cell treatment, a process known as protective autophagy. On the carcinoma, which occurs at a high rate of >90% (5). Moreover, other hand, autophagy overactivation may lead to cell death, 70‑80% of new cases are diagnosed as non‑muscle invasive referred to as autophagic cell death, similar to apoptosis. BC (NMIBC) (6‑8). Despite undergoing transurethral resec- Therefore, it is essential to identify the role of autophagy in tion of bladder tumor, up to 50% of patients with NMIBC cancer cells in order to develop novel therapeutic agents. In can experience relapse, and 20% continue to progress within addition, autophagy may potentially become a novel thera- 5 years (9). The risk factors for NMIBC progression include peutic target in human diseases. In this review, the current tumor stage, grade, size, number and recurrence rate (10). knowledge on autophagy modulation in BC development and A multidisciplinary approach for the reduction of the tumor treatment is summarized. recurrence rate, involving surgical intervention combined with radiotherapy, chemotherapy or immunotherapy, is a therapeutic option in patients with BC (10,11). Nevertheless, Contents such a treatment tactic still has unsatisfactory clinical effects. Thus, the development of novel therapies and enhancement of 1. Introduction responses to current therapies is urgently required, in order to 2. Autophagy overview improve clinical outcomes. 3. Autophagy signaling pathways Autophagy, a fundamental evolutionary catabolic process, 4. Autophagy regulation in BC plays an important role in the maintenance of cellular envi- 5. Conclusions ronmental homeostasis by degrading and recycling damaged cytoplasmic components, including macromolecules and organelles (12). This process can be activated by various cellular stress conditions, including nutrient deprivation (13,14), organelle damage (15), radiotherapy or chemotherapy (15,16), to satisfy cellular needs and promote cell survival. The role of autophagy in cancer development and therapy appears to be Correspondence to: Dr Honglan Zhou, Department of Urology, paradoxical depending on the context. During the initial stage The First Hospital of Jilin University, 71 Xinmin Street, Changchun, of cancer development, autophagy serves a major role in tumor Jilin 130021, P. R. China E‑mail: [email protected] suppression by maintaining genomic integrity and preventing proliferation and inflammation (17). However, after the estab- Key words: autophagy, bladder cancer, autophagosome, lysosome, lishment of cancer, cancer cells may utilize autophagy to autophagic cell death survive cellular stresses in the adverse microenvironment (18). In addition, autophagy is considered a double‑edged sword with regard to the treatment of cancer. Cellular protective autophagy induced by anticancer therapy plays an important 1648 LI et al: AUTOPHAGY MODULATION IN BLADDER CANCER DEVELOPMENT AND TREATMENT role in therapy resistance among cancer cells. Thus, autophagy (Fig. 3) (26,27). Presumably, ATG8‑phosphatidylethanolamine inhibition can increase the sensitivity of cancer cells to anti- (PE), a useful marker of autophagic membranes, is involved in cancer therapy. On the contrary, autophagy promotion may almost all steps of the autophagic flux, particularly the later steps, induce type II programmed cell death, which is referred to including phagophore expansion and lysosome fusion (26). as autophagic cell death, similar to apoptosis (19). In this In addition, more than 30 autophagy-related genes and review, the current knowledge on autophagy modulation in BC homologous proteins have been identified to be essential development and treatment is summarized, with the aim of for autophagy (28). Therefore, the activation of autophagy exploring novel and potential therapeutic targets. in response to various stresses leads to alterations in the expression levels of autophagy-related proteins, including 2. Autophagy overview microtubule-associated protein light chain 3 (LC3), p62 and Beclin1. As a member of the ATG8 family in mammals, LC3 Autophagy is a lysosomal degradation process in which is a specific protein marker of autophagosome formation. damaged, long-lived cytoplasmic proteins and organelles are In the ATG8 ubiquitin‑like conjugation system, LC3 is first swallowed by double‑membrane autophagic vesicles termed cleaved by ATG4, a specific cysteine protease, to expose the autophagosomes (20). The fusion of an autophagosome with a C-terminal cysteine. Subsequently, LC3 is conjugated to PE lysosome results in the formation of an autolysosome, which by ATG7 and ATG3, facilitating the conversion of cytosolic provides an acidic environment for hydrolytic enzymes to LC3-I to membrane-bound LC3-II (Fig. 3) (29). p62, also degrade the internalized cellular components (21). Autophagy referred to as sequestosome 1, is a multi-functional signaling is a biological phenomenon widely occurring in eukaryotic protein implicated in cell proliferation, survival and death. cells. In addition, it is a fascinating process regulated by Recent studies have revealed that p62 plays a critical role multiple autophagy-related proteins. in the autophagic proteolytic cascade by binding to and According to the mode of transport for intracellular delivering ubiquitinated contents to autophagosomes. p62 components to the lysosome, the following three important interacts with membrane protein LC3 via its LC3‑interacting subtypes of autophagy in mammals have been identified: region motif (30-32). Therefore, p62 degradation occurs in Macroautophagy, microautophagy and chaperone‑mediated autolysosomes. On the contrary, autophagy inhibition is often autophagy (CMA) (Fig. 1). Macroautophagy, which is usually accompanied by upregulation of p62 expression. Beclin1, referred to as autophagy, is the main autophagy pathway. a multi‑domain protein, regulates the cross talk between During this pathway, the cell forms a double‑membrane autophagy and apoptosis. Additionally, the class III PI3K structure termed a phagophore, which develops into an complex has been identified as an important signaling hub that autophagosome. Subsequently, cytoplasmic components are regulates the autophagy‑flux and balances the processes of engulfed into autophagosomes and delivered to lysosomes for autophagy and apoptosis. Therefore, as a PI3K‑III regulatory fusion and degradation. Nevertheless, there is a fundamental subunit, Beclin1 plays an important role in the regulation of difference between micro‑ and macroautophagy. In microau- autophagy through phosphorylation and ubiquitination (33). tophagy, the lysosome membrane autonomously changes shape via invagination or bulging to engulf cytoplasmic components 3. Autophagy signaling pathways directly. CMA is a selective and unique autophagic process that selectively discerns and degrades substrate proteins Autophagy is induced under conditions of cellular stress, containing the specific KFERQ pentapeptide sequence. Heat including hypoxia, oxidative stress, nutrient deprivation, shock cognate protein of 70 kDa, a cytosolic chaperone protein, organelle damage and radiotherapy or chemotherapy in order is a key component in CMA able to discern the KFERQ motif to meet cellular needs and promote cell survival. Moreover, and deliver it to lysosome associated membrane protein type 2 autophagy levels are regulated by these cellular stresses for degradation (22,23). Owing to its easily recognizable through different signaling pathways. Subsequently, once double-membrane vesicles, macroautophagy is the best-char- these stresses are eliminated by autophagy upregulation, levels acterized variant of autophagy. The unique morphological return to normal. features of macroautophagy have been the focus of numerous studies since 1950 (24). Moreover, macroautophagy is the mTOR signaling pathway. mTOR is a 300-kDa serine/threonine