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S100A8 Promotes Chemoresistance Via Augmenting Autophagy in B‑Cell Lymphoma Cells

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S100A8 Promotes Chemoresistance Via Augmenting Autophagy in B‑Cell Lymphoma Cells ONCOLOGY REPORTS 45: 151-158, 2021 S100A8 promotes chemoresistance via augmenting autophagy in B‑cell lymphoma cells LI ZHANG1,2, SHIXIA ZHOU3, TIEJUN ZHOU4, KAIFENG YUAN3, XIAOMING LI3 and JUNLING TANG3 1Hospital of Stomatology, Southwest Medical University; Departments of 2Oral and Maxillofacial Surgery, 3Haematology and 4Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China Received June 15, 2020; Accepted October 9, 2020 DOI: 10.3892/or.2020.7841 Abstract. B-cell lymphomas (BCLs) are malignant lymphoid self-replicating abilities (1-4). Despite advances in treatment, tumours originating from the malignant proliferation and the quality of life of the patients following treatment is highly transformation of mature lymphocytes at various stages of affected by chemotherapy resistance, which severely impedes differentiation and clonal expansion of the lymphatic and circu- the clinical treatment of B-cell lymphomas (BCLs) (5-7). latory systems. Efforts to control or even eradicate BCLs are BCLs comprise a heterogenous group of mature lymphopro- frequently hampered by the development of drug resistance. liferative malignancies that are among the top 10 causes of Autophagy is an evolutionarily conserved biological process cancer-related mortality, mainly occurring in the lymph nodes, of the energy metabolism. By degrading intracellular organ- spleen, thymus and other lymphoid organs (4,8,9). Almost all elles and proteins, autophagy provides cells with biochemical anti-lymphoma treatments are accompanied by chemotherapy reaction substrates for the maintenance of homeostasis under resistance, including resistance to genotoxic agents, mono- nutrient deprivation or other stressful conditions. Accumulating clonal antibodies, antibody-drug conjugates, targeted agents evidence indicates that autophagy plays an important role in or multidrug combinations (5,10-12). Chemotherapy resistance chemotherapy resistance. S100A8 is an important member of has become the most important challenge to the successful the calcium-binding protein family that plays an important role treatment of BCLs. in regulating tumour resistance to chemotherapy, while the Autophagy is an evolutionarily conserved biological specific molecular regulatory mechanisms remain unclear. In process of the energy metabolism (13,14). By degrading the present study, by employing three BCL cell lines (Daudi, intracellular organelles and proteins, autophagy provides cells SUDHL-4 and JeKo-1), it was demonstrated that BCL cells with biochemical reaction substrates for the maintenance with a strong drug resistance also exhibited active autophagy. of homeostasis under nutrient deficiencies or other stress In addition, S100A8 was found to be crucial for regulating drug conditions (15,16). Autophagy has been confirmed to play a resistance and promoting autophagy in BCL cells. Interference pivotal role in chemotherapy resistance (17). The inhibition of S100A8 significantly downregulated Bcl‑2/adenovirus E1B of autophagy may enhance the cytotoxicity of chemotherapy 19-kDa protein-interacting protein 3 located in the mitochondria drugs and the apoptosis of multiple malignant tumour and endoplasmic reticulum to further inhibit autophagy. In addi- cells, including BCL cells (18). Various studies have also tion, S100A8 interference markedly inhibited the formation of demonstrated that multiple chemotherapeutic drugs increase the BECN1‑PI3KC3 complex and promoted B‑cell lymphoma 2 autophagic flux, thereby enhancing drug resistance and expression, which collectively inhibited autophagy. promoting cell survival (19,20). Autophagy-related 5 (ATG5) is a protein that, in humans, is Introduction encoded by the ATG5 gene located on chromosome 6. ATG5 acts as a proviral factor in the autophagic vesicle formation Haematological malignancies comprise a group of process. Conjugation with ATG12, through a ubiquitin-like heterogeneous tumours with prominent proliferative and conjugating system involving ATG7 as an E1-like activating enzyme and ATG10 as an E2-like conjugating enzyme, is crucial for the function of ATG5 (21,22). The ATG5-ATG12 conjugate acts as an E3-like enzyme, which is required for the Correspondence to: Dr Junling Tang, Department of Haematology, lipidation of the ATG8 family of proteins and their association The Affiliated Hospital of Southwest Medical University, 25 Tai with the vesicle membranes (23,24). This ATG5-ATG12 conju- Ping Street, Luzhou, Sichuan 646000, P.R. China gate is necessary for the conjugation of microtubule-associated E-mail: [email protected] protein 1A/1B‑light chain 3 (LC3)‑I and phosphatidylethanol- amine to form LC3‑II (23,25). Key words: S100A8, chemoresistance, autophagy, non-Hodgkin S100A8 is a multifunctional, calcium-binding protein lymphoma that polymerizes with S100A9 to form calprotectin for the sequestration of metals, including iron, manganese and zinc, via chelation (26). S100A8 is part of the 22-member 152 ZHANG et al: S100A8 PROMOTES CHEMORESISTANCE VIA AUTOPHAGY IN B‑CELL LYMPHOMA CELLS calcium‑binding EF hand‑containing S100 superfamily of Scientific, Inc.) were used for lentivirus packaging in 293T proteins, which functions predominantly in the innate immune cells. The supernatant of the 293T culture was collected and system (27). S100A8 is expressed in varying degrees in a variety filtered using a 0.22‑µm filter (EMD Millipore), followed by a of cells, and is abundant in myeloid cells (28). According to concentration step. Medium containing lentivirus was stored previous reports, S100A8 is mainly involved in cell prolif- at ‑80˚C for future use. eration and inflammation, and participates in the occurrence and development of various types of cancer (29). S100A8 has Reverse transcription quantitative PCR (RT‑qPCR) analysis. been shown to be associated with myeloid differentiation, Total RNA was isolated using TRIzol® (Takara Bio, Inc.) and autophagy, apoptosis and chemotherapy resistance (30-32). reverse‑transcribed into cDNA using PrimeScript RT Master The Bcl-2/adenovirus E1B 19-kDa protein-interacting Mix (Takara Bio, Inc.). according to the manufacturer's protein 3 (BNIP3) is a BH3‑only protein primarily localized to instructions. RT-qPCR was performed using SYBR Green the mitochondria and endoplasmic reticulum (ER). BNIP3 is Real‑time PCR Master Mix kit (Takara Bio, Inc.), according to anchored to the outer mitochondrial and ER membrane via its the manufacturer's instructions. The following PCR conditions C-terminus transmembrane domain, whereas the N-terminus were used on the Light Cycler: 39 cycles at 95˚C for 30 sec, faces the cytosol. BNIP3 induces cell death by perturbing 95˚C for 5 sec, followed by 60˚C for 30 sec in a 10‑µl reac- mitochondrial function (33,34). The abnormal expression and tion volume. The relative expression was normalized to that of function of BNIP3 may interfere with Ca2+ homeostasis and GAPDH, which was used as the internal control. The primers promote cell death (35,36). BNIP3 is also a potent inducer of used were as follows: ATG5, 5'-CTC TGC AGT GGC TGA GTG autophagy in multiple types of cells (32,37). AA-3' forward and 5'-TCA ATC TGT TGG CTG TGG GA-3' The aim of the present study was to determine the role of reverse; S100A8, 5'‑CCG AGC TGG AGA AAG CCT T G ‑ 3 ' S100A8 in the chemotherapy resistance of BCLs by inves- forward and 5'‑AGG TCA TCC CTG TAG ACG GC‑3' reverse; tigating whether the resistance of BCL cells to Adriamycin GAPDH, 5'-AGA AGG CTG GGG CTC ATT TG-3' forward and (ADR) and vincristine (VCR) was positively correlated with 5'-AGG GGC CAT CCA CAG TCT TC-3' reverse. autophagy, and whether S100A8 activates autophagy in BCL cells by promoting BNIP3, Beclin‑1 (BECN1) and class III Western blotting (WB). Cells were lysed in SDS lysis buffer phosphatidylinositol‑3‑kinase (PI3KC3) expression, hoping to (P0013G; Beyotime Institute of Biotechnology) containing identify a novel target for the treatment of BCLs. 1% protease inhibitor PMSF (ST506; Beyotime Institute of Biotechnology). The extracted protein concentration Materials and methods was determined using the BCA protein assay kit (P0012S; Beyotime Institute of Biotechnology) and stored at ‑80˚C. A Cell lines and cell culture. Daudi, SUDHL-4 and JeKo-1 cells total of 20 µg of each protein sample was separated by 12% were purchased from the Cell Bank of the Chinese Academy SDS‑PAGE and transferred to PVDF membranes (IPVH00010; of Sciences (Shanghai, China) and cultured in RPMI‑1640 EMD Millipore). Following blocking with 5% non‑fat milk medium supplemented with 10% FBS (Gibco; Thermo Fisher for 1 h at room temperature, the membranes were incubated Scientific, Inc.) and 2 mM glutamine in a humidified incubator with appropriate primary and secondary antibodies. Proteins with 5% CO2 and 95% air. were detected using an enhanced chemiluminescence kit (6305; Bio‑Rad Laboratories, Inc.) under a gel electrophoresis Cell viability assay. Cell viability was assessed by MTT assay. imager (Bio‑Rad Laboratories, Inc.). The primary antibodies Daudi, SUDHL-4 and JeKo-1 cells were plated in 96-well for LC3 (source, rabbit; cat. no. ab192890; dilution, 1:1,000), plates at a density of 2x103 cells per well containing 100 µl P62 (cat. no. ab207305; source, rabbit; dilution, 1:2,000) and culture medium. ADR (1 mg/ml) or VCR (1 mg/ml) was added calnexin (source, rabbit; cat. no. ab13504; dilution, 1:2,000) to 96-well culture plates with 10 µl per well and incubated for were purchased from Abcam. The primary antibodies for 72 h, followed by incubation with MTT. The control cells were B‑cell lymphoma 2 (BCL2; cat. no. 12789‑1‑AP; source, rabbit; treated only with PBS prior to incubation with MTT. Dimethyl dilution, 1:500), BECN1 (cat. no. 11306‑1‑AP; source, rabbit; sulfoxide was used to dissolve the formazan. The relative dilution, 1:500), PI3KC3 (cat. no. 20584‑1‑AP; source, rabbit; cell viability was calculated by measuring the absorbance dilution, 1:100) and tubulin (cat. no. 10068‑1‑AP; source, rabbit; value/well at 570 nm and using the following equation: Mean dilution, 1:2,000) were purchased from ProteinTech Group, optical density (OD) of treated cells/mean OD of control cells.
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