Upregulated miR-182 increases drug resistance in cisplatin-treated HCC cell by regulating TP53INP1

Chemotherapy plays a crucial role in hepatocellular carcinoma (HCC) treatment especially for patients with advanced HCC. Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of HCC. However, acquisition of cisplatin resistance is common in patients with HCC, and the underlying mechanism of such resistance is not fully understood. In the study, we focused on identifying the role of miRNAs in chemotherapy resistance after cisplatin-based combination chemotherapy. We assayed the expression level of miR-182 after cisplatin-based chemotherapy in patients with advanced HCC, and defined the biological functions by real-time PCR analysis and CCK-8 assay. We found that miR-182 levels were significantly increased in HCC patients treated with cisplatin-based chemotherapy. miR-182 levels were also higher in cisplatin-resistant HepG2 (HepG2-R) cells than in HepG2 cells. Upregulated miR-182 significantly increased the cell viability, whereas miR-182 knockdown reduced the cell viability during cisplatin treatment. miR-182 inhibition also partially overcame cisplatin resistance in HepG2-R cell. Furthermore, we found that upregulated miR-182 inhibited the expression of tumor suppressor gene TP53INP1 (tumor protein 53-induced nuclear protein1) in vitro. In vivo, miR-182 and TP53INP1 expression was negatively correlated. We finally demonstrated that miR-182 increased cisplatin resistance of HCC cell, partly by targeting TP53INP1. These data suggest that miR-182/TP53INP1 signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.     

Upregulated miR-130a increases drug resistance by regulating RUNX3 and Wnt signaling in cisplatin-treated HCC cell

Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of patients with advanced liver cancer. However, acquisition of cisplatin resistance is common in patients with hepatocellular carcinoma (HCC), and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-130a levels were significantly increased in HCC patients treated with cisplatin-based chemotherapy. miR-130a levels were also higher in cisplatin-resistant Huh7 cells than in Huh7 cells. Overexpression of miR-130a contributed to cisplatin resistance in Huh7 cell, whereas knockdown of miR-130a overcame cisplatin resistance in cisplatin-resistant Huh7 cell. We further demonstrated that upregulated miR-130a directly inhibited expression of tumor suppressor gene RUNX3, which resulted in activation of Wnt/β-catenin signaling and increased drug resistance. These data suggest that miR-130a/RUNX3/Wnt signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.     

Inhibition of mitochondrial respiration overcomes hepatocellular carcinoma chemoresistance

The clinical management of advanced hepatocellular carcinoma (HCC) is challenging due to its resistance to chemotherapy. In our work, we demonstrate that an antiparasitic drug atovaquone at clinically relevant concentrations is active against chemoresistant HCC. We show that atovaquone inhibits proliferation and induces apoptosis in not only HCC parental cells but also cells exposed to long time culture of chemotherapeutic agents. Consistently, the combination of atovaquone with cisplatin or doxorubicin achieved remarkably greater efficacy than single drug alone. Mechanistically, atovaquone overcomes HCC chemoresistance via supressing mitochondrial respiration and inducing oxidative stress. Atovaquone but not cisplatin or doxorubicin is ineffective in mitochondrial respiration-deficient ρ0, confirming mitochondria as a specific upstream target of atovaquone. Interestingly, we show that prolonged exposure of HCC cells to chemotherapeutic agents induces higher level of mitochondrial respiration, suggesting that tumors which develop chemoresistance after chemotherapy might be more dependent on mitochondrial respiration than primary tumors and explaining the sensitivity of chemoresistant HCC cells to atovaquone. We further show that atovaquone at tolerable does significantly inhibits chemoresistant HCC growth in mice throughout the duration of treatment. In line with in vitro data, we observe the increased oxidative stress in atovaquone-treated tumors. Our findings highlight the dependency of chemoresistant HCC on mitochondrial respiration and demonstrate that atovaquone is a potential drug to overcome HCC chemoresistance.     

Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/β-catenin signaling

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In this study, we found that nuclear accumulation of β-catenin was higher in cisplatin-resistant Huh7 cells than in Huh7 cells, indicating that Wnt signaling was activated in cisplatin-resistant cells. Wnt signaling inhibition increased cisplatin-induced growth inhibition in hepatoma cell. We further demonstrated that sorafenib could inhibit Wnt signaling in Huh7 cells and cisplatin-resistant Huh7 cells. Co-treatment with cisplatin and sorafenib was more effective in inhibiting cancer cell proliferation than cisplatin alone in vitro and in vivo, whereas Wnt3a (Wnt activator) treatment abrogated sorafenib-induced growth inhibition. These data demonstrated that sorafenib sensitizes human HCC cell to cisplatin via suppression of Wnt/β-catenin signaling, thus offering a new target for chemotherapy of HCC.     

Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.     

Epstein-Barr Virus_Encoded LMP1 Upregulates MicroRNA-21 to Promote the Resistance of Nasopharyngeal Carcinoma Cells to Cisplatin-Induced Apoptosis by Suppressing PDCD4 and Fas-L

Approximately 30% of patients with Epstein-Barr virus (EBV)-positive advanced nasopharyngeal carcinoma (NPC) display chemoresistance to cisplatin-based regimens, but the underlying mechanisms are unclear. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), a functional homologue of the tumor necrosis factor receptor family, contributes substantially to the oncogenic potential of EBV through the activation of multiple signaling pathways, and it is closely associated with a poorer prognosis for NPC. Recent studies show that EBV infection can induce the expression of many cellular miRNAs, including microRNA-21, a biomarker for chemoresistance. However, neither a link between LMP1 expression and miR-21 upregulation nor their cross talk in affecting chemoresistance to cisplatin have been reported. Here, we observed that stable LMP1-transformed NPC cells were less sensitive to cisplatin treatment based on their proliferation, colony formation, the IC₅₀ value of cisplatin and the apoptosis index. Higher levels of miR-21 were found in EBV-carrying and LMP1-positive cell lines, suggesting that LMP1 may be linked to miR-21 upregulation. These data were confirmed by our results that exogenous LMP1 increased miR-21 in both transiently and stably LMP1-transfected cells, and the knock down of miR-21 substantially reversed the resistance of the NPC cells to cisplatin treatment. Moreover, the proapoptotic factors programmed cell death 4 (PDCD4) and Fas ligand (Fas-L), which were negatively regulated by miR-21, were found to play an important role in the program of LMP1-dependent cisplatin resistance. Finally, we demonstrated that LMP1 induced miR-21 expression primarily by modulating the PI3K/AKT/FOXO3a signaling pathway. Taken together, we revealed for the first time that viral LMP1 triggers the PI3K/Akt/FOXO3a pathway to induce human miR-21 expression, which subsequently decreases the expression of PDCD4 and Fas-L, and results in chemoresistance in NPC cells.     

Galectin-1 overexpression promotes progression and chemoresistance to cisplatin in epithelial ovarian cancer

This study was performed to investigate the role of galectin-1 (Gal-1) in epithelial ovarian cancer (EOC) progression and chemoresistance. Tissue samples from patients with EOC were used to examine the correlation between Gal-1 expression and clinical stage of EOC. The role of Gal-1 in EOC progression and chemoresistance was evaluated in vitro by siRNA-mediated knockdown of Gal-1 or lentivirus-mediated overexpression of Gal-1 in EOC cell lines. To elucidate the molecular mechanisms underlying Gal-1-mediated tumor progression and chemoresistance, the expression and activities of some signaling molecules associated with Gal-1 were analyzed. We found overexpression of Gal-1 in advanced stages of EOC. Knockdown of endogenous Gal-1 in EOC cells resulted in the reduction in cell growth, migration, and invasion in vitro, which may be caused by Gal-1''s interaction with H-Ras and activation of the Raf/extracellular signal-regulated kinase (ERK) pathway. Additionally, matrix metalloproteinase-9 (MMP-9) and c-Jun were downregulated in Gal-1-knockdown cells. Notably, Gal-1 overexpression could significantly decrease the sensitivities of EOC cells to cisplatin, which might be ascribed to Gal-1-induced activation of the H-Ras/Raf/ERK pathway and upregulation of p21 and Bcl-2. Taken together, the results suggest that Gal-1 contributes to both tumorigenesis and cisplatin resistance in EOC. Thus, Gal-1 is a potential therapeutic target for EOC.     

Bmi1 Essentially Mediates Podocalyxin-Enhanced Cisplatin Chemoresistance in Oral Tongue Squamous Cell Carcinoma

Oral tongue squamous cell carcinoma (OTSCC) is one of the most common head and neck cancers. Innate or acquired resistance to cisplatin, a standard chemotherapy agent for OTSCC, is common in patients with OTSCC. Understanding the molecular basis for cisplatin chemoresistance in OTSCC cells may serve as a basis for identification of novel therapeutic targets. Podocalyxin (PODXL) has been found critical for malignant progression in a variety of cancers. Bmi1 has recently been found to induce cell apoptosis and cisplatin chemosensitivity in OTSCC cells. In this study, we explored the interaction between PODXL and Bmi1 in OTSCC cells, and assessed its impact on OTSCC cell chemoresistance to cisplatin. PODXL and/or Bmi1 were stably overexpressed or knocked down in SCC-4 and Tca8113 human OTSCC cells. Overexpression of PODXL in both cell lines markedly elevated the expression level of Bmi1 and the half maximal inhibitory concentration (IC50) of cisplain and reduced cisplatin-induced cell apoptosis, which was abolished by knockdown of Bmi1 or a selective focal adhesion kinase (FAK) inhibitor. On the other hand, knockdown of PODXL significantly decreased the Bmi1 expression level and cisplatin IC50 and increased cisplatin-induced cell apoptosis, which was completely reversed by overexpression of Bmi1. While overexpression and knockdown of PODXL respectively increased and decreased the FAK activity, Bmi1 showed no significant effect on the FAK activity in OTSCC cells. In addition, overexpression of PODXL markedly elevated the stability of Bmi1 mRNA, which was abolished by a selective FAK inhibitor. In conclusion, this study provides the first evidence that PODXL up-regulates the expression level of Bmi1 in OTSCC cells by increasing the stability of Bmi1 mRNA through a FAK-dependent mechanism; this effect leads to enhanced cisplatin chemoresistance in OTSCC cells. This study adds new insights into the molecular mechanisms underlying OTSCC chemoresistance.     

MicroRNA‐760 Inhibits Doxorubicin Resistance in Hepatocellular Carcinoma through Regulating Notch1/Hes1‐PTEN/Akt Signaling Pathway

Accumulating studies have suggested that microRNA‐760 (miR‐760) plays an important role in chemoresistance of various cancer cells. However, whether miR‐760 regulates the chemoresistance of hepatocellular carcinoma (HCC) remains unclear. In this study, we found that miR‐760 was decreased in HCC cell lines, and doxorubicin (Dox) treatment significantly decreased miR‐760 expression in HCC cells. Overexpression of miR‐760 sensitized HCC cells to Dox‐induced cytotoxicity and apoptosis, whereas miR‐760 inhibition showed the opposite effects. Notch1 was predicted as a target gene of miR‐760. miR‐760 negatively regulated Notch1 expression and Notch1/Hes1 signaling. Overexpression of miR‐760 increased PTEN expression and decreased the phosphorylation of Akt. Activation of Notch signaling significantly reversed the inhibitory effect of miR‐760 on Dox‐resistance and abrogated the effect of miR‐760 on the PTEN/Akt signaling pathway in HCC cells. Overall, our results demonstrate that miR‐760 inhibits Dox‐resistance in HCC cells through inhibiting Notch1 and promoting PTEN expression.     

Pyruvate dehydrogenase kinase 1 contributes to cisplatin resistance of ovarian cancer through EGFR activation

Patients with ovarian cancer frequently develop acquired drug resistance after the long-term chemotherapy, leading to disease progression. Enhanced epithelial–mesenchymal transition (EMT) has been implicated in chemoresistance of ovarian cancer cells; however, the molecular mechanisms involved are largely undefined. Pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, has been recognized as a gatekeeper of the Warburg effect, a hallmark of cancer. In this study, the function of PDK1 in cisplatin resistance of ovarian cancer in terms of growth and EMT was investigated. PDK1 was upregulated in cisplatin-resistant ovarian cancer cells. PDK1 knockdown in resistant cells led to increased sensitivity to cisplatin-induced cell death and apoptosis. PDK1 downregulation also reversed the EMT and cell motility in cisplatin-resistant cells. In a mouse xenograft model, tumors derived from PDK1-silenced ovarian cancer cells exhibited decreased tumor growth and EMT compared with control after the cisplatin treatment. Mechanistically, PDK1 overexpression led to increased phosphorylation of EGFR, and blocking EGFR kinase activity by erlotinib reversed cisplatin resistance induced by PDK1 overexpression. Furthermore, in patients with ovarian cancer, higher PDK1 and p-EGFR levels were associated with chemoresistance. These results supported that PDK1 contributes to chemoresistance of ovarian cancer by activating EGFR. Therefore, PDK1 may serve as a promising target to combat chemoresistance of ovarian cancer.     

Platycodin D reverses histone deacetylase inhibitor resistance in hepatocellular carcinoma cells by repressing ERK1/2-mediated cofilin-1 phosphorylation

BackgroundChemoresistance remains the main obstacle in hepatocellular carcinoma (HCC) therapy. Despite significant advances in HCC therapy, HCC still has a poor prognosis. Thus, there is an urgent need to identify a treatment target to reverse HCC chemotherapy resistance. Platycodon grandiflorus (PG) is a perennial herb that has been used as food and traditional Chinese medicine for thousands of years in Northeast Asia. Platycodin D (PD), a main active triterpenoid saponin found in the root of PG, has been reported to possess anticancer properties in several cancer cell lines, including HCC; however, the reversal effect of this molecule on HCC chemoresistance remains largely unknown.PurposeThis study aimed to investigate the role and the mechanism of PD-mediated reversal of the histone deacetylase inhibitor (HDACi) resistance in HCC cells.MethodsHuman HCC cells (HA22T) and HDACi-resistant (HDACi-R) cells were used. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Combination index was used to calculate the synergism potential. Expression of ERK1/2 (total/phospho), cofilin-1 (total/phospho) and apoptosis-related protein was determined using western blotting. Mitochondrial membrane potential was assessed using the JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide) probe. Apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Mitochondrial reactive oxygen species generation was measured using the MitoSOX Red fluorescent probe.ResultsWe found that PD treatment inhibited cell viability both in HA22T HCC and HDACi-R cells. Inhibition of ERK1/2 by PD98059 could reverse drug resistance in HDACi-R cells treated with PD98059 and PD. Nevertheless, pre-treatment with U46619, an ERK1/2 activator, rescued PD-induced apoptosis by decreasing levels of apoptosis-related proteins in HCC cells. The combined treatment of PD with apicidin a powerful HDACi, dramatically enhanced the apoptotic effect in HDACi-R cells.ConclusionFor the first time, we showed that PD reversed HDACi resistance in HCC by repressing ERK1/2-mediated cofilin-1 phosphorylation. Thus, PD can potentially be a treatment target to reverse HCC chemotherapy resistance in future therapeutic trials.     

GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy

Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFRα1 (GDNF family receptor α 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy. GFRA1 regulates AMPK-dependent autophagy by promoting SRC phosphorylation independent of proto-oncogene RET kinase. Cisplatin-resistant osteosarcoma cells showed NFKB1/NFκB-mediated GFRA1 expression. GFRA1 expression promoted tumor formation and growth in mouse xenograft models and inhibition of autophagy in a GFRA1-expressing xenograft mouse model during cisplatin treatment effectively reduced tumor growth and increased survival. In cisplatin-treated patients, treatment period and metastatic status were associated with GFRA1-mediated autophagy. These findings suggest that GFRA1-mediated autophagy is a promising novel target for overcoming cisplatin resistance in osteosarcoma.     

MicroRNA-181a enhances the chemoresistance of human cervical squamous cell carcinoma to cisplatin by targeting PRKCD

MicroRNAs(miRNAs) are involved in regulating the response of cancer cells to various therapeutic interventions, but their involvement in the chemoresistance of human cervical squamous cell carcinoma is not fully understood. We found miR-181a was significantly up-regulated in specimens from patients with chemoresistant cervical squamous cell carcinoma. In this study, we aimed to clarify the role of miR-181a in regulating the chemoresistance of cervical cancer. Two human cervical squamous cancer cell lines, SiHa and Me180, were used. Enforced expression of miR-181a enhanced chemoresistance to cisplatin in cervical cancer cells through apoptosis reversion. In a nude mouse xenograft model, the overexpression of miR-181a markedly inhibited the therapeutic response to cisplatin. PRKCD, a target gene of miR-181a and a promoter of apoptosis, was negatively regulated by miR-181a. We found that the effect of miR-181a on chemoresistance was mediated by PRKCD. Additionally, silencing of PRKCD yielded an effect similar to that of miR-181a up-regulation and inhibited apoptosis in cervical cancer cells. Our findings suggest that miR-181a may function as an oncogene and induce chemoresistance in cervical squamous cell carcinoma cells at least in part by down-regulating PRKCD, thus may provide a biomarker for predicting chemosensitivity to cisplatin in patients with cervical squamous cancer.     

Deregulation of lncRNA-AC078883.3 and microRNA-19a is involved in the development of chemoresistance to cisplatin via modulating signaling pathway of PTEN/AKT

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. As a platinum-based chemotherapeutic drug, cisplatin has been used in the NSCLC treatment for over 30 years, and its effects are impaired by drug resistance. This study aimed to investigate the potential role of lncRNA-AC078883.3 in the development of chemoresistance against cisplatin. Real-time PCR, Western blot analysis, Immunohistochemistry (IHC) assay, bioinformatic analysis, and luciferase assay were collaboratively used to establish the lncRNA-AC078883.3/miR-19a/PTEN/AKT pathway. Also, the effect of cisplatin on cell proliferation was observed via an MTT assay. Furthermore, Cox regression and Kaplan–Meier analyses were used to study whether lncRNA-AC078883.3 is involved in the survival of NSCLC. Compared with the Cisplatin-Sensitive group, the Cisplatin-Resistance group exhibited lower levels of lncRNA-AC078883.3 and PTEN and higher levels of miR-19a and p-Akt. The growth rate of A549 and H460 cells and the IC ₅₀ of DPP in the Cisplatin-Resistance group were higher than those in the Cisplatin-S group. miR-19a contains a putative binding site of lncRNA-AC078883.3, which enabled the luciferase activity of wild-type lncRNA-AC078883.3 to be reduced by miR-19a. In addition, by directly targeting PTEN 3′-untranslated region (UTR), miR-19a repressed the luciferase activity of wild-type PTEN 3′-UTR. The median OS of patients with reduced lncRNA-AC078883.3 expression was longer than that of patients with higher lncRNA-AC078883.3 expression. Finally, compared with low lncRNA-AC078883.3-expression patients, the high lncRNA-AC078883.3-expression patients were associated with lower miR-19a expression and higher PTEN expression. Therefore, we suggested for the first time that the low expression of lncRNA-AC078883.3 contributed to the development of chemoresistance against cisplatin.     

Modulation of Myb-induced NF-kB -STAT3 signaling and resulting cisplatin resistance in ovarian cancer by dietary factors

c-Myb regulates tumorigenesis in multiple cancers. Here we show, for the first time, the mechanism of c-Myb-mediated proliferation, invasion, and drug resistance in ovarian cancer (OC), the most lethal gynecological cancer, and a comparative analyses of dietary agents, curcumin, epigallocatechin-3-gallate (EGCG), and sulforaphane in inhibiting c-Myb activity. We evaluated myb expression in patients with OC and found its increased expression in patients with cancer, compared with normal controls and in higher grade tumors, compared with low-grade tumors. Using ES2 and OVCAR3 cell line models, along with the silencing or overexpression of c-Myb, we establish a role of c-Myb in determining resistance to cisplatin. c-Myb overexpression activated NF-κB and STAT3 signaling leading to enhanced proliferation, invasion, and cisplatin resistance. Contrary to this, silencing of c-Myb inhibited proliferation, invasion, and sensitized OC cells to cisplatin. Further, among the dietary agents tested, EGCG almost completely inhibited the c-Myb-induced proliferation and invasion whereas sulforaphane also had significant inhibitory effect. Both compounds significantly sensitized OC cells to cisplatin, reversing the c-Myb effects. Higher c-Myb levels in patients with ovarian cancer lead to poor survival and our results indicate a possible effect of dietary factors EGCG and sulforaphane against c-Myb-mediated ovarian cancer progression and chemoresistance.     

Oncogenic gene TRIM10 confers resistance to cisplatin in osteosarcoma cells and activates the NF-κB signaling pathway

Deregulation of tripartite motif (TRIM) family proteins contribute to multiple biological processes such as neurodegeneration, development, inflammation, cell survival, apoptosis, and carcinogenesis. However, the biological function and molecular mechanism of TRIM family proteins in osteosarcoma chemoresistance remain unclear. In the current study, we found the protein expression of TRIM10 was markedly overexpressed in cisplatin resistance's osteosarcoma tissues and TRIM10 overexpression was inversely correlated with osteosarcoma patient survival. Furthermore, overexpression of TRIM10 confers cisplatin resistance on osteosarcoma cells; however, repressing TRIM10 sensitized osteosarcoma cell lines to cisplatin cytotoxicity in vitro. Mechanically, TRIM10 upregulated the nuclear levels of p65, thereby activating canonical NF-κB signaling. Taken together, our results suggest that TRIM10 contributed to cisplatin resistance in osteosarcoma cells, and targeting the TRIM10/p65 axis may represent a promising strategy to enhance cisplatin response in osteosarcoma patients with chemoresistance.     

Roles of aldo-keto reductases 1B10 and 1C3 and ATP-binding cassette transporter in docetaxel tolerance

Docetaxel (DTX) is widely used for treatment of inveterate lung and prostate cancers, but its continuous administration elicits the hyposensitivity. Here, we established the DTX-resistant variants of human lung cancer A549 and androgen-independent prostate cancer Du145 cells and found that the resistance development provoked aberrant up-regulations of aldo-keto reductase (AKR) 1B10 and AKR1C3 in A549 and Du145 cells, respectively. In addition, the sensitivity to the DTX toxicity was significantly decreased and increased by overexpression and knockdown of the two AKR isoforms, respectively. Furthermore, the resistant cells exhibited a decreased level of reactive 4-hydroxy-2-nonenal formed during DTX treatment, and the decrease was alleviated by adding the AKR inhibitors, inferring that the two AKRs confer the chemoresistance through elevating the antioxidant properties. The development of DTX resistance was also associated with enhanced expression of an ATP-binding cassette (ABC) transporter ABCB1 among the ABC transporter isoforms. The combined treatment with inhibitors of the two AKRs and ABCB1 additively sensitized the resistant cells to DTX. Intriguingly, the AKR1B10 inhibitor also suppressed the lung cancer cross-resistance against cisplatin. The results suggest that combined treatment with AKRs (1B10 and 1C3) and ABCB1 inhibitors exerts overcoming effect against the cancer resistance to DTX and cisplatin, and can be used as the adjuvant therapy.     

Sophoridine suppresses lenvatinib-resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression

Hepatocellular carcinoma (HCC) is one of the most lethal cancer types with insufficient approved therapies, among which lenvatinib is a newly approved multi-targeted tyrosine kinase inhibitor for frontline advanced HCC treatment. However, resistance to lenvatinib has been reported in HCC treatment recently, which limits the clinical benefits of lenvatinib. This study aims to investigate the underlying mechanism of lenvatinib resistance and explore the potential drug to improve the treatment for lenvatinib-resistant (LR) HCC. Here, we developed two human LR HCC cell lines by culturing with long-term exposure to lenvatinib. Results showed that the vascular endothelial growth factor receptors (VEGFR)2 expression and its downstream RAS/MEK/ERK signalling were obviously up-regulated in LR HCC cells, whereas the expression of VEGFR1, VEGFR3, FGFR1-4 and PDGFRα/β showed no difference. Furthermore, ETS-1 was identified to be responsible for VEGFR2 mediated lenvatinib resistance. The cell models were further used to explore the potential strategies for restoration of sensitivity of lenvatinib. Sophoridine, an alkaloid extraction, inhibited the proliferation, colony formation, cell migration and increased apoptosis of LR HCC cells. In vivo and in vitro results showed Sophoridine could further sensitize the therapeutic of lenvatinib against LR HCC. Mechanism studies revealed that Sophoridine decreased ETS-1 expression to down-regulate VEGFR2 expression along with downstream RAS/MEK/ERK axis in LR HCC cells. Hence, our study revealed that up-regulated VEGFR2 expression could be a predicator of the resistance of lenvatinib treatment against HCC and provided a potential candidate to restore the sensitivity of lenvatinib for HCC treatment.