Targeting autophagy is a promising therapeutic strategy to overcome chemoresistance and reduce metastasis in osteosarcoma

Abstract

Osteosarcoma (OS) is the most common primary bone malignancy, mainly affecting children and adolescents. Currently, surgical resection combined with adjuvant chemotherapy has been standardized for OS treatment. Despite great advances in chemotherapy for OS, its clinical prognosis remains far from satisfactory; this is due to chemoresistance, which has become a major obstacle to improving OS treatment. Autophagy, a catabolic process through which cells eliminate and recycle their own damaged proteins and organelles to provide energy, can be activated by chemotherapeutic drugs. Accumulating evidence has indicated that autophagy plays the dual role in the regulation of OS chemoresistance by either promoting drug resistance or increasing drug sensitivity. The aim of the present review was to demonstrate thatautophagy has both a cytoprotective and an autophagic cell death function in OS chemoresistance. In addition, methods to detect autophagy, autophagy inducers and inhibitors, as well as autophagy‑mediated metastasis, immunotherapy and clinical prognosis are also discussed.

Figure 1

Autophagy-related proteins, and autophagy inducers and inhibitors involved in the autophagic process. Autophagy is initiated by the ULK1 complex and the class III PI3K complex. The former is composed of ULK1/2, ATG13, ATG101 and FIP200, and the latter of Beclin-1, VPS34, p150, UVRAG, BIF1, ATG14L and rubicon. Autophagosome formation is controlled by the ATG12 and LC3 conjugation systems. ATG2, ATG9 and ATG18 are involved in autolyso-some formation, and p62 and NBR1 in the regulation of degradation and recycling. Rapamycin activates autophagy by inhibiting mTOR, a negative regulator of the ULK1 complex. 3-MA, LY294002, wortmannin and spautin-1 suppress early autophagy by inhibiting the class III PI3K complex. Chloroquine and bafilomycin A1 inhibit late autophagy by blocking the fusion of autophagosomes and lysosomes. ULK1, UNC-51-like kinase; ATG, autophagy-related protein; FIP200, focal adhesion kinase family interacting protein of 200; VPS34, vacuolar protein sorting 34; UVRAG, ultraviolet irradiation resistance-associated gene; BIF1, BAX-interacting factor-1; ATG14L, ATG14-like protein; rubicon, Run domain Beclin-1-interacting and cysteine-rich domain-containing protein; mTOR, mammalian target of rapamycin; 3-MA, 3-methyladenine; NBR1, neighbor of BRCA1 protein.

Figure 2

Autophagy regulates OS chemoresistance, metastasis and tumor immunity. HMGB1, GFRA1, HMGN5, IGF2, DNA-PKcs, NDRG1 and HSP90AA1 induced by chemotherapeutic drugs activate cytoprotective autophagy and contribute to chemoresistance in OS. In addition, miRNAs increase OS chemosensitivity by either inhibiting cytoprotective autophagy or inducing autophagic cell death. NVP-BEZ235 (a PI3K/mTOR inhibitor), TSSC3 and certain Chinese herbs enhance chemosensitivity in OS by increasing apoptosis which is dependent of autophagic cell death. COPS3 knockdown and metformin reduce autophagy-mediated metastasis in OS. Polymeric chloroquine decreased CXCR4-mediated OS metastasis, and this effect was autophagy-independent. PD-L1 suppression by 3-MA and PD-L2 knockdown enhanced immunological response and inhibited OS metastasis. HMGB1, High mobility group box 1; GFRA1, GDNF receptor α1; HMGN5, high-mobility group nucleosome-binding domain 5; IGF2, insulin growth factor 2; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; miRNA, microRNA; NDRG1, N-myc downstream-regulated gene 1; HSP90AA1, heat shock protein 90AA1; OS, osteosarcoma; TSSC3, tumor-suppressing STF cDNA 3; COPS3, COP9 signalosome subunit 3; CXCR4, chemokine receptor 4; PD-L, programmed death ligand; 3-MA, 3-methyladenine.