Salvianolic acid B suppresses EMT and apoptosis to lessen drug resistance through AKT/mTOR in gastric cancer cells

The drug resistance of tumor cells greatly reduces the efficacy of chemotherapy drugs in gastric cancer. Salvianolic acid B (Sal-B) is considered as a chemopreventive agent which suppresses oxidative stress and apoptosis. Therefore, the study aims to clarify the mechanism of Sal-B in drug-resistant gastric cancer cells. CCK8 assay analyzed cell viabilities after GES1, AGS and AGS/DDP cells were respectively treated by Sal-B of different concentration or after AGS/DDP cells were disposed by cisplatin (DDP) in different concentration. The colony formation, ROS generation, apoptosis, migration, invasion and EMT marker proteins were respectively analyzed through formation assay, ROS kits, TUNNEL staining, Wound healing, Transwell assays and Western blot. The results demonstrated that Sal-B acted alone or in synergy with DDP to reduce cell viabilities, initiate ROS generation, promote cell apoptosis, as well as decrease migration, invasion and EMT in AGS and AGS/DDP cells. AKT activator and mTOR activator significantly reversed the above effects of Sal-B. Collectively, Sal-B regulated proliferation, EMT and apoptosis to reduce the resistance to DDP via AKT/mTOR pathway in DDP-resistant gastric cancer cells. Sal-B could be a potential anti-drug resistance agent to chemotherapy in gastric cancer.     

山奈酚对胃癌细胞PARP1以及P53基因表达的影响研究

胃癌(GC)是最常见的恶性肿瘤之一,是人类健康的主要威胁,其发病机制是一个单基因或多基因逐步突变的过程,与细胞的侵袭、增殖和转移有关,包括癌基因遗传和表观遗传的突变、肿瘤抑制基因、DNA修复途径基因、细胞周期途径基因和幽门螺杆菌感染等。而山奈酚具有多种生物学活性,能够抑制多种肿瘤细胞的细胞周期,诱导肿瘤细胞凋亡从而抑制肿瘤细胞/组织的侵袭及转移。因此本研究用不同浓度的山奈酚处理胃癌细胞,并检测了胃癌细胞的形态变化情况、癌细胞凋亡相关因子P53和PARP1基因的表达水平和其对应的蛋白质表达变化。结果表明大于100μmol/L山奈酚处理后的胃癌细胞中P53基因和P53蛋白的表达水平被显著提高,而相反的PARP1基因和蛋白的表达则被显著抑制,且山奈酚处理后胃癌细胞的凋亡数目也明显增加,因此本实验结果表明,山奈酚能够有效的促进胃癌细胞凋亡的发生,以此来达到抑制癌细胞恶性增殖的作用。这一结果可以为后续针对胃癌新疗法的研究提供一些思路和理论支持。     

A proteomic kinetic analysis of IGROV1 ovarian carcinoma cell line response to cisplatin treatment

Ovarian cancer is one of the leading causes of mortality by gynecological cancer. Despite good response to surgery and initial chemotherapy, essentially based on cisplatin (cis-diamino-dichloro-platinum(II) (CDDP)) compounds, frequent recurrences with chemoresistance acquisition are responsible for poor prognosis. Several mechanisms have been described as implicated in CDDP resistance, however they are not sufficient to exhaustively account for this resistance emergence. We applied a proteomic approach based on 2-DE coupled with MS (MALDI-TOF/TOF) to identify proteins associated with chemoresistance induced by CDDP. A kinetic analysis of IGROV1 cell behavior following treatment with CDDP and subsequent statistical analysis revealed time and/or concentration-dependent modifications in protein expression. We evidenced events such as decreased amino-acid and nucleotide synthesis potentially associated with cell cycle blockade, and variations that may be related to resistance acquisition, such as possible enhanced glycolysis and increased proliferating potential. Moreover, overexpressions of aldehyde dehydrogenase 1 and both cytokeratins 8 and 18 were consistent with our previous findings, demonstrating that expression of these proteins was increased in cisplatin-resistant IGROV1-R10 as compared to IGROV1 parental cells. Identification of such proteins could allow improved understanding of the mechanisms leading to cell death or survival and, thus, to the acquisition of chemoresistance.     

和厚朴酚调控Nrf2/ARE通路对胃癌细胞的顺铂化疗敏感性的影响

目的探讨和厚朴酚调节核转录相关因子2 （Nrf2）/抗氧化反应元件（ARE）通路对胃癌细胞顺铂耐药的影响。 方法体外培养人胃癌顺铂耐药细胞SGC7901/DDP,采用5 μg/mL、15 μg/mL和厚朴酚及15 μg/mL和厚朴酚联合1 mmol/L Nrf2/ARE通路激活剂富马酸二甲酯（DMF）进行干预;MTT法检测细胞增殖;划痕实验、Transwell小室检测细胞迁移、侵袭;流式细胞仪检测细胞凋亡;Western blot检测细胞Nrf2、血红素加氧酶1 （HO-1）、P-糖蛋白（P-gp）、多药耐药相关蛋白1 （MRP1）、增殖细胞核抗原（PCNA）、基质金属蛋白酶2 （MMP2）、基质金属蛋白酶9 （MMP9）、半胱氨酸蛋白酶3 （caspase-3）和活化的caspase-3 （cleaved caspase-3）的表达;构建SGC7901/DDP移植瘤裸鼠模型,随机分为对照组、低剂量和厚朴酚组、高剂量和厚朴酚组、Nrf2/ARE通路激活剂组,分组处理后检测其肿瘤体积与重量。单因素方差分析和Tukey检验用于多组间的比较。 结果与对照组比较,低、高剂量和厚朴酚组OD₄₉₀值、划痕愈合率[（31.24 ± 2.23）%、（25.36 ± 2.06）%比（48.01 ± 2.13）%]、侵袭率[（38.61 ± 2.24）%、（29.57 ± 2.41）%比（52.36 ± 2.13）%]、肿瘤体积与质量、HO-1、P-gp、MRP1、PCNA、MMP2、MMP9、核Nrf2蛋白表达均降低（P均< 0.05）,凋亡率[（27.24 ± 2.24）%、（38.56 ± 2.31）%比（17.31 ± 3.12）%]、caspase-3和cleaved caspase-3蛋白表达升高（P < 0.05）;与高剂量和厚朴酚组比较,Nrf2/ARE通路激活剂组的OD₄₉₀值、划痕愈合率[（37.71 ± 2.17）%比（25.36 ± 2.06）%]、侵袭率[（43.53 ± 2.37）%比（29.57 ± 2.41）%]、肿瘤体积与质量、HO-1、P-gp、MRP1、PCNA、MMP2、MMP9和核Nrf2蛋白表达均升高（P < 0.05）,凋亡率[（21.48 ± 2.16）%比（38.56 ± 2.31）%]、caspase-3和cleaved caspase-3蛋白表达降低（P均< 0.05）。 结论和厚朴酚可能通过调控Nrf2/ARE信号通路进而影响胃癌耐药细胞株SGC7901/DDP的顺铂化疗敏感性。     

KDM2A对人卵巢癌顺铂耐药细胞株A2780增殖和凋亡的影响及机制研究

目的:探讨赖氨酸脱甲基酶2A(Lysine-specific demethylase 2A,KDM2A)对顺铂(cisplatin,DDP)耐药的人卵巢癌细胞A2780细胞增殖和凋亡的影响及其可能作用机制。方法:通过构建慢病毒载体转染A2780/DDP,分为A2780、A2780/DDP、A2780/DDP/KDM2A(转染KDM2A)、A2780/DDP/Jagged1(转染Jagged1)以及A2780/DDP/NC(转染病毒载体)组。采用Western blot检测3组KDM2A、Jagged1、Bcl2和BAX蛋白表达,CCK8和平板克隆形成实验检测细胞对顺铂的敏感性,流式细胞术检测细胞凋亡情况。结果:A2780/DDP细胞KDM2A和Jagged1的蛋白表达水平均显著高于A2780细胞(P0.05),且A2780/DDP/KDM2A细胞中KDM2A和Jagged1的蛋白表达均低于A2780/DDP以及阴性对照组A2780/DDP/NC(P0.05);A2780/DDP/Jagged1细胞的Jagged1蛋白表达低于A2780/DDP以及A2780/DDP/NC(P0.05),而其KDM2A蛋白的表达比较差异无统计学意义(P0.05)。不同浓度DDP处理的A2780/DDP/KDM2A细胞的生长抑制率均显著高于A2780/DDP/NC和A2780/DDP细胞(P0.05),A2780/DDP/KDM2A细胞克隆形成数量亦明显高于A2780/DDP/NC和A2780/DDP细胞(P0.05)。A2780/DDP/KDM2A细胞凋亡率为(25.84±3.27)%,明显高于A2780/DDP细胞[(14.29±1.96)%](P0.05)和A2780/DDP/NC细胞[(12.46±2.15)%](P0.05)。A2780/DDP/KDM2A细胞中Bcl-2蛋白表达明显低于A2780/DDP细胞(P0.05),而A2780/DDP/KDM2A细胞Bax的表达水平却高于A2780/DDP细胞(P0.05)。结论:KDM2A可能通过上调Jagged1的表达,促进人卵巢癌细胞A2780的增殖并抑制其凋亡,进而降低人卵巢癌耐药细胞A2780的顺铂敏感性。     

Comparative proteomic analysis of cisplatin sensitive IGROV1 ovarian carcinoma cell line and its resistant counterpart IGROV1-R10

Ovarian cancer is one of the leading causes of mortality due to gynaecological cancer. Despite a good response to surgery and initial chemotherapy essentially based on cisplatin (cis-diamino-dichloro-platinum(II) (CDDP)) compounds, late tumour detection and frequent recurrences with chemoresistance acquisition are responsible for poor prognosis. Several mechanisms have been implicated in CDDP resistance but they are not sufficient to exhaustively explain this resistance emergence. We applied a proteomic approach based on 2-DE coupled with MS to identify proteins associated with the chemoresistance process. We first established a proteomic pattern of the CDDP sensitive ovarian cell line IGROV1 using MALDI-TOF-MS and PMF. We then compared this 2-D pattern with that of the CDDP-resistant counterpart IGROV1-R10. Among the 40 proteins identified, cytokeratins 8 and 18 and aldehyde dehydrogenase 1 were overexpressed in IGROV1-R10, whereas annexin IV was down-regulated. These observations have been confirmed by Western blotting. The characterization of such variations could lead to the development of new protein markers or to the establishment of new therapeutic strategies. Moreover, the identification of proteins involved in CDDP resistance in ovarian tumours would be useful in completing our understanding on this complex mechanism.     

Reduced inhibition of DNA synthesis and G2 arrest during the cell cycle of resistant HeLa cells in response tocis-diamminedichloroplatinum

The influence of cisplatin, an anticancer agent, on DNA synthesis and cell cycle progression of a cisplatin-resistant cell line was investigated. Cell cycle analysis using flow cytometry showed that cytotoxic concentrations of cisplatin caused a transient inhibition of parental HeLa cells at S phase, followed by accumulation at G₂ phase. In contrast, the resistant cells progressed through the cell cycle without being affected by the same treatment. However, cell cycle distributions were the same in the resistant and the parental cells at IC₅₀, the drug concentration inhibiting cell growth by 50%. Studies using a [³H]thymidine incorporation technique also demonstrated a transient inhibition of DNA synthesis in HeLa cells by cisplatin; such inhibition was greatly reduced in the resistant cells. These data argue for the hypothesis that the inhibition of DNA synthesis is important in determining cisplatin-induced cytotoxicity. In addition, the accumulation of cells at G₀/G₁ by serum starvation was not effective in the resistant cells compared to the parental cells, suggesting that the control of cell cycle exiting is also altered in the resistant cells. Taken together, these results support the notion that alterations in cell cycle control, in particular G₂ arrest, are important in determining the sensitivity or resistance of mammalian cells to cisplatin and may have a role in clinical protocols.     

siRNA抑制S100A4表达对卵巢癌细胞CP70生物学特性的影响

目的：探讨人卵巢癌顺铂耐药细胞株CP70沉默S100A4基因后,CP70细胞对顺铂敏感性、凋亡及细胞迁移的影响。方法：设计并合成S100A4基因特异性的siRNA并转染入卵巢癌细胞CP70,48 h后应用RT-PCR和Western Blot检测在mRNA和蛋白水平siRNA对S100A4的影响,MTT法检测转染siRNA后卵巢癌细胞CP70对顺铂敏感性的变化。用流式细胞术检测顺铂（40μM）对转染S100A4 siRNA后对卵巢癌细胞CP70凋亡的影响,Transwell法观察siRNA抑制S100A4后对卵巢癌CP70迁移能力的影响。结果：与空白对照组、阴性对照组相比,S100A4siRNA转染组CP70细胞的S100A4基因和蛋白表达降低（P〈0.01）。MTT法检测顺铂敏感性发现S100A4 siRNA转染组CP70细胞顺铂敏感性增强。在顺铂刺激下,siRNA转染组细胞凋亡率高于其他各组,差异具有统计学意义（P〈0.05）。Transwell发现CP70细胞迁移能力明显下降（P〈0.05）。结论：S100A4 siRNA能够明显抑制CP70细胞S100A4的表达,从而增强细胞对顺铂的敏感性,促进细胞凋亡,减弱细胞的迁移能力。S100A4有望成为逆转卵巢癌铂类耐药的治疗靶点。     

Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer

Background

Somatic mutation in mitochondrial DNA (mtDNA) has been proposed to contribute to initiation and progression of human cancer. In our previous study, high frequency of somatic mutations was found in the D-loop region of mtDNA of gastric cancers. However, it is unclear whether somatic mutations occur in the coding region of mtDNA of gastric cancers.

Methods

Using DNA sequencing, we studied 31 gastric cancer specimens and corresponding non-cancerous stomach tissues. Moreover, a human gastric cancer SC-M1 cell line was treated with oligomycin to induce mitochondrial dysfunction. Cisplatin sensitivity and cell migration were analyzed.

Results

We identified eight somatic mutations in the coding region of mtDNAs of seven gastric cancer samples (7/31, 22.6%). Patients with somatic mutations in the entire mtDNA of gastric cancers did not show significant association with their clinicopathologic features. Among the eight somatic mutations, five point mutations (G3697A, G4996A, G9986A, C12405T and T13015C) are homoplasmic and three mutations (5895delC, 7472insC and 12418insA) are heteroplasmic. Four (4/8, 50%) of these somatic mutations result in amino acid substitutions in the highly conserved regions of mtDNA, which potentially lead to mitochondrial dysfunction. In addition, in vitro experiments in SC-M1 cells revealed that oligomycin-induced mitochondrial dysfunction promoted resistance to cisplatin and enhanced cell migration. N-acetyl cysteine was effective in the prevention of the oligomycin-enhanced migration, which suggests that reactive oxygen species generated by defective mitochondria may be involved in the enhanced migration of SC-M1 cells.

General Significance

Our results suggest that somatic mtDNA mutations and mitochondrial dysfunction may play an important role in the malignant progression of gastric cancer.     

IL-18 enhances thrombospondin-1 production in human gastric cancer via JNK pathway

IL-18 is a pleiotropic cytokine that is produced by many cancer cells. A recent report suggested that IL-18 plays a key role in regulating the immune escape of melanoma and gastric cancer cells. Thrombospondin (TSP-1) is known to inhibit angiogenesis in several cancers but some studies have reported that it stimulates angiogenesis in some cancers such as gastric cancer. IL-18 and TSP-1 are related to tumor proliferation and metastasis. This study investigated the relationship between IL-18 and TSP-1 in gastric cancer. RT-PCR and ELISA showed that after the cells had been treated with IL-18, the level of TSP-1 mRNA expression and TSP-1 protein production by IL-18 increased in both a dose- and time-dependent manner. The cells were next treated with specific inhibitors in order to determine the signal pathway involved in IL-18-enhanced TSP-1 production. IL-18-enhanced TSP-1 expression was blocked by SP600125, a c-Jun N-terminal kinase (JNK) specific inhibitor. In addition, Western blot showed that IL-18 enhanced the expression of phosphorylated JNK. Overall, these results suggest that IL-18 plays a key role in TSP-1 expression involving JNK.     

HMGA1通过Wnt/β-Catenin通路被诱导并维持胃癌细胞增殖

目的探讨HMGA1通过Wnt/β-Catenin通路在胃肿瘤形成中的作用。方法应用小干扰RNA介导的基因沉默、细胞增殖分析、PCR等技术完成实验。结果 HMGA1的特异敲除明显减少细胞生长。β-Catenin或下游c-myc的损失减少HMGA1表达,而Wnt3a处理增加HMGA1和c-myc的转录。结论这些数据表明,HMGA1参与胃癌细胞形成和增殖通过Wnt/β-Catenin通路。     

Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) independent of downstream damage response (DDR) pathways

The treatment for advanced stage non-small cell lung cancer (NSCLC) often includes platinum-based chemotherapy and IR. Cisplatin and IR combination therapy display schedule and dose-dependent synergy, the mechanism of which is not completely understood. In a series of in vitro and cell culture assays in a NSCLC model, we investigated both the downstream and direct treatment and damage effects of cisplatin on NHEJ catalyzed repair of a DNA DSB. The results demonstrate that extracts prepared from cisplatin-treated cells are fully capable of NHEJ catalyzed repair of a DSB using a non-cisplatin-damaged DNA substrate in vitro. Similarly, using two different host cell reactivation assays, treatment of cells prior to transfection of a linear, undamaged reporter plasmid revealed no reduction in NHEJ compared with untreated cells. In contrast, transfection of a linear GFP-reporter plasmid containing site-specific, cisplatin lesions 6-bp from the termini revealed a significant impairment in DSB repair of the cisplatin-damaged DNA substrates in the absence of cellular treatment with cisplatin. Together, these data demonstrate that impaired NHEJ in combined cisplatin-IR treated cells is likely the result of a direct effect of cisplatin-DNA lesions near a DSB and that the indirect cellular effects of cisplatin treatment are not significant contributors to the synergistic cytotoxicity observed with combination cisplatin-IR treatment.     

LINC00665/miR-379-5p/GRP78 regulates cisplatin sensitivity in gastric cancer by modulating endoplasmic reticulum stress

Cytotechnology - Acquired resistance to cisplatin (DDP)-based chemotherapy greatly hinders the treatment of gastric cancer (GC). LINC00665 serves as an oncogene in GC. Hence, the current study was...     

Solution behaviour and biological activity of bisamidine complexes of platinum(II)

A series of platinum(II) amidine complexes were previously prepared with the aim of obtaining a new class of platinum-based antitumour drugs. This series includes compounds of the type cis--[PtCl2{Z-HN=C(NHMe)Me}2] and trans-[PtCl2{Z-HN=C(NHMe)Me}2] (1, 2), cis-[PtCl2{E-HN=C(NMe2)Me}2] and trans-[PtCl2{E-HN=C(NMe2)Me}2] (3, 4), cis-[PtCl2{Z-HN=C(NHMe)Ph}2] and trans-[PtCl2{Z-HN=C(NHMe)Ph}2] (5, 6), and cis-[PtCl2{HN=C(NMe2)Ph}2] and trans-[PtCl2{HN=C(NMe2)Ph}2] (7, 8). The reactions with dimethyl sulfoxide were studied for complexes 5-8; the formation of cationic species containing coordinated dimethyl sulfoxide was demonstrated by NMR experiments and electrospray ionization mass spectrometry. In this work, the amidine platinum(II) complexes were tested for their in vitro cytotoxicity on a panel of various human cancer cell lines. The results indicate that the benzamidine complex 8 was the most effective derivative also circumventing acquired cisplatin resistance as demonstrated by chemosensitivity tests performed on cisplatin-sensitive and cisplatin-resistant cell lines. The studies concerning the cellular DNA damage on both parental chemosensitive and resistant sublines suggest for the new trans-amidine complex a different mechanism of action compared with that exhibited by cisplatin.     

5-氮杂-2＇-脱氧胞苷对卵巢癌细胞系CP70顺铂耐药性的逆转作用

目的：探究5-氮杂-2＇-脱氧胞苷体外逆转卵巢癌铂类耐药细胞系CP70对顺铂的耐药性,并探讨与SOCS-2表达的关系。方法：免疫细胞化学和Western blot方法检测使用5-氮杂-2＇-脱氧胞苷处理细胞前后细胞内SOCS-2表达水平。MTT法检测单独使用5-氮杂-2＇-脱氧胞苷或顺铂及两药联合使用对CP70细胞的抑制作用。结果：两药联合处理CP70细胞后顺铂耐药逆转倍数为1.34、1.63、2.34,联合处理组的细胞中SOCS-2表达明显升高。结论：5-氮杂-2＇-脱氧胞苷可以部分逆转CP70细胞对顺铂的耐药性,且此作用可能与增加细胞的SOCS-2表达有关。     

5- 氮杂-2'－脱氧胞苷对卵巢癌细胞系CP70 顺铂耐药性的逆转作用

目的:探究5-氮杂-2’-脱氧胞苷体外逆转卵巢癌铂类耐药细胞系CP70对顺铂的耐药性,并探讨与SOCS-2表达的关系。方法:免疫细胞化学和Western blot方法检测使用5-氮杂-2’-脱氧胞苷处理细胞前后细胞内SOCS-2表达水平。MTT法检测单独使用5-氮杂-2’-脱氧胞苷或顺铂及两药联合使用对CP70细胞的抑制作用。结果:两药联合处理CP70细胞后顺铂耐药逆转倍数为1.34、1.63、2.34,联合处理组的细胞中SOCS-2表达明显升高。结论:5-氮杂-2’-脱氧胞苷可以部分逆转CP70细胞对顺铂的耐药性,且此作用可能与增加细胞的SOCS-2表达有关。     

Protein arginine methyltransferase 1 coordinates the epithelial-mesenchymal transition/proliferation dichotomy in gastric cancer cells

Protein arginine methyltransferase 1 (PRMT1) is up-regulated and promotes migration, invasion and proliferation in wide range of cancers. However, we for the first time identify that PRMT1 promotes migration and invasion and inhibits proliferation in gastric cancer cells, a phenomenon called “migration-proliferation dichotomy”. First, we find that PRMT1 overexpression promotes migration and invasion and inhibits proliferation, whereas PRMT1 knockdown reverses the above abilities. Next, PRMT1 reduces the expression of epithelial marker E-cadherin and increases the expression of mesenchymal markers including N-cadherin, Vimentin, snail and β-catenin in gastric cancer cells. Furthermore, our studies show that PRMT1 silencing promotes the phosphorylation of LATS1, and then induces YAP phosphorylation, while overexpression of PRMT1 down-regulates the phosphorylation of LATS1 and YAP, indicating that PRMT1 inhibits EMT probably via Hippo signaling. Collectively, the present study reveals important roles of PRMT1 in progression of gastric cancer. Given the dual functions of PRMT1, it is as a potential drug target of gastric cancer with extreme caution.     

SIRT1在宫颈癌细胞耐药中的作用及其机制研究

摘要目的：探讨沉默交配型信息调节因子2同源蛋白1（silentmatingtypeinformationregulation2homologyl,SIRTl）在宫颈癌化疗耐药中的作用及其机制。方法：体外培养人宫颈癌Hela细胞系和宫颈癌Hela／MMC耐药细胞亚系,westernblotting检测MMC对Hela和Hela／MMC细胞内SIRTl蛋白表达的影响;MTT法检测MMC及Nicotinamide对Hela和Hela／MMC细胞增殖的影响;AnnexinV-PI试验检测Hela／MMC细胞凋亡的亡的情况;RT—PCR方法检测耐药相关蛋白P—gP的mRNA表达情况。结果：正常情况下,Hela／MMC细胞中SIRTl的表达显著高于Hela细胞（P〈0．05）,MMC处理的Hela／MMC细胞中SIRTl的表达显著高于未经MMC处理（P〈0．05）。Nicotinamide对Hela和Hela／MMC细胞具有相似的生长抑制作用,Nicotinamide可使MMC诱导的Hela／MMC细胞凋亡增加,同时降低细胞内P-gP的mRNA表达（P〈0．05）。结论：SIRTl表达下调能显著减轻Hela／MMC细胞对MMC的耐药性,其作用可能与P—gp有关。     

PAXX is a novel target to overcome resistance to doxorubicin and cisplatin in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor diagnosed in children and adolescents. Unfortunately, OS patients with metastatic or recurrent disease are highly resistant to front line chemotherapy that significantly limits the long-term survival rate. Since majority of chemotherapeutic agents used in OS work by generating DNA damages, enhanced DNA repair pathways are generally associated with chemoresistance in OS treatment. However, the exact mechanisms of chemoresistance in OS are not fully understood. Our study found that paralogue of XRCC4 and XLF (PAXX), which was identified recently as a novel factor of non-homologous end joining (NHEJ), is upregulated in chemoresistant OS cells. Importantly, PAXX deficiency re-sensitizes chemoresistant OS cells to doxorubicin and cisplatin. Mechanistically, chemoresistance to doxorubicin or cisplatin results in enhanced PAXX-Ku70 interaction and elevated NHEJ efficiency. We also identified a small molecule M11 that interrupts PAXX-Ku70 interaction and re-sensitizes chemoresistant OS cells to doxorubicin and cisplatin. Thus, our data provide evidence that PAXX could serve as a novel target to overcome chemoresistance in OS treatment.