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Review
. 2019 Nov;42(5):1647-1655.
doi: 10.3892/or.2019.7286. Epub 2019 Aug 21.

Autophagy modulation in bladder cancer development and treatment (Review)

Faping Li  1 , Hui Guo  1 , Yuxuan Yang  1 , Mingliang Feng  1 , Bin Liu  1 , Xiang Ren  1 , Honglan Zhou  1
Affiliations
Review

Autophagy modulation in bladder cancer development and treatment (Review)

Faping Li et al. Oncol Rep. 2019 Nov.

Abstract

Bladder cancer (BC) is a potentially life‑threatening malignancy. Due to a high recurrence rate, frequent surveillance strategies and intravesical drug therapies, BC is considered one of the most expensive tumors to treat. As a fundamental evolutionary catabolic process, autophagy plays an important role in the maintenance of cellular environmental homeostasis by degrading and recycling damaged cytoplasmic components, including macromolecules and organelles. Scientific studies in the last two decades have shown that autophagy acts as a double‑edged sword with regard to the treatment of cancer. On one hand, autophagy inhibition is able to increase the sensitivity of cancer cells to treatment, a process known as protective autophagy. On the other hand, autophagy overactivation may lead to cell death, referred to as autophagic cell death, similar to apoptosis. Therefore, it is essential to identify the role of autophagy in cancer cells in order to develop novel therapeutic agents. In addition, autophagy may potentially become a novel therapeutic target in human diseases. In this review, the current knowledge on autophagy modulation in BC development and treatment is summarized.

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Figures

Figure 1.
Figure 1.
Three main subtypes of autophagy. Long-lived and damaged cytoplasmic components are degraded via different autophagic processes. The diagram presents the three main subtypes: Macroautophagy, microautophagy and CMA. In macroautophagy, a double-membrane vesicle (phagophore) surrounds degradation components to form an autophagosome, which fuses with a lysosome for subsequent hydrolysis. In microautophagy, the lysosomal membrane alters its shape via invagination or bulging to engulf cytoplasmic components for degradation. In CMA, the adapter molecule HSC70 discerns and binds to the specific KFERQ motif of substrate proteins for translocation to the lysosome and ensures binding to Lamp2 for degradation. CMA, chaperone-mediated autophagy; HSC70, heat shock cognate protein of 70 kDa; Lamp2, lysosome associated membrane protein type 2.
Figure 2.
Figure 2.
Steps of the autophagic flux. Autophagy is activated in response to various cellular stress conditions. A double-membrane vesicle (phagophore) begins to form and elongate into an autophagosome in order to engulf intracellular degradation components, including mitochondria, damaged organelles and lipid droplets. The mature autophagosome with intracellular degradation components then fuses with the lysosome and forms an autolysosome, which provides an acidic environment for hydrolytic enzymes to hydrolyze the engulfed components.
Figure 3.
Figure 3.
Signaling pathways of autophagy. mTOR kinase is a pivotal molecule in the mTORC1 complex that plays an important role in the regulation of autophagy. Autophagy activation is triggered by decreased activity of the mTORC1 complex due to the activation of AMPK or p53 signaling. The decreased activity of mTORC1, an inhibitor of the mammalian ULK1 complex, leads to the increase the activity of the ULK1 complex, which subsequently initiates the formation of phagophore in conjunction with the PI3K complex. The elongation and maturation of the phagophore is dependent on two ubiquitin-like conjugation systems (ATG12 and ATG8), which involve multiple autophagy proteins, including ATG5, ATG16 and LC3. ATG, autophagy-related protein homolog; mTORC1, mTOR complex 1; AMPK, AMP-activated protein kinase; ULK1, uncoordinated-51-like protein kinase; LC3, microtubule-associated protein light chain 3; PE, phosphatidylethanolamine; TTI1, Tel2-interacting protein 1; TEL2, telomere length regulation protein TEL2; DEPTOR, DEP domain-containing mTOR-interacting protein; RAPTOR, regulatory-associated protein of mTOR; PRAS40, proline-rich Akt substrate of 40 kDa; MLST8, mTOR-associated protein LST8 homolog; MAPK, mitogen-activated protein kinase; FIP200, fusion-inhibiting peptide 200.
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