scholarly journals Paradoxical effects of DNA tumor virus oncogenes on epithelium-derived tumor cell fate during tumor progression and chemotherapy response

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jiang He ◽  
Liyu Liu ◽  
Feiyu Tang ◽  
You Zhou ◽  
Huan Liu ◽  
...  

AbstractEpstein-Barr virus (EBV) and human papillomavirus (HPV) infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma, respectively. However, clinical analyses demonstrate that EBV or HPV is associated with improved response of patients, although underlying mechanism remains unclear. Here, we reported that the oncoproteins of DNA viruses, such as LMP1 of EBV and E7 of HPV, inhibit PERK activity in cancer cells via the interaction of the viral oncoproteins with PERK through a conserved motif. Inhibition of PERK led to increased level of reactive oxygen species (ROS) that promoted tumor and enhanced the efficacy of chemotherapy in vivo. Consistently, disruption of viral oncoprotein-PERK interactions attenuated tumor growth and chemotherapy in both cancer cells and tumor-bearing mouse models. Our findings uncovered a paradoxical effect of DNA tumor virus oncoproteins on tumors and highlighted that targeting PERK might be an attractive strategy for the treatment of NPC and cervical carcinoma.

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaokun Wang ◽  
Dongjuan Qiao ◽  
Likun Chen ◽  
Meng Xu ◽  
Shupeng Chen ◽  
...  

Abstract Background Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process. Methods Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting. Results Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy. Conclusions Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.


2016 ◽  
Vol 0 (0) ◽  
Author(s):  
Min Yang ◽  
Nan Jiang ◽  
Qi-wei Cao ◽  
Qing Sun

Abstract Gastric cancer is the most common digestive malignant tumor worldwild. EDD1 was reported to be frequently amplified in several tumors and played an important role in the tumorigenesis process. However, the biological role and potential mechanism of EDD1 in gastric cancer remains poorly understood. In this study, we are aim to investigate the effect of EDD1 on gastric cancer progression and to explore the underlying mechanism. The results showed the significant up-regulation of EDD1 in -gastric cancer cell tissues and lines. The expression level of EDD1 was also positively associated with advanced clinical stages and predicted poor overall patient survival and poor disease-free patient survival. Besides, EDD1 knockdown markedly inhibited cell viability, colony formation, and suppressed tumor growth. Opposite results were obtained in gastric cancer cells with EDD1 overexpression. EDD1 knockdown was also found to induce gastric cancer cells apoptosis. Further investigation indicated that the oncogenic role of EDD1 in regulating gastric cancer cells growth and apoptosis was related to its PABC domain and directly through targeting miR-22, which was significantly down-regulated in gastric cancer tissues. Totally, our study suggests that EDD1 plays an oncogenic role in gastric cancer and may be a potential therapeutic target for gastric cancer.


2019 ◽  
Vol 51 (12) ◽  
pp. 1276-1285
Author(s):  
Xiaolan Ouyang ◽  
Xiaoming Hao ◽  
Shuaibin Liu ◽  
Jianguo Hu ◽  
Lina Hu

Abstract Cervical cancer is a prevalent and devastating malignancy in females worldwide. Nucleoporin 93 (Nup93), a member of the nuclear pore complex, plays an important role in transport across the nuclear pore. Several nucleoporins have been linked to cancer. However, the oncogenic role and underlying mechanism of Nup93 in cervical cancer development have not been reported. In this study, the expression of Nup93 was analyzed by quantitative real-time polymerase chain reaction (qPCR), western blot analysis, and immunohistochemical staining in cervical cancer tissues and cell lines. We found that the expression of Nup93 was higher in cervical cancer samples, compared to normal cervical samples. The knockdown of Nup93 inhibited cell proliferation, migration, and invasion capacity of cervical cancer cells. At the same time, we also found that silencing of Nup93 could inhibit cellular migration and invasion by regulating cytoskeleton actin and Rho family proteins. Nup93 also participated in the IL-6/STAT3 signaling pathway. In addition, down-regulation of Nup93 prevented tumor formation in mice in vivo. Thus, Nup93 may be a carcinogenic gene and serve as a potential therapeutic target for cervical cancer.


2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Junya Ning ◽  
Zhaomin Lin ◽  
Xuan Zhao ◽  
Baoxiang Zhao ◽  
Junying Miao

Abstract The level of hypochlorous acid (HOCl) in cancer cells is higher than that in non-cancer cells. HOCl is an essential signal for the regulation of cell fate and works mainly through the protein post-translational modifications in cancer cells. However, the mechanism of HOCl regulating autophagy has not been clarified. Here we reported that a HOCl probe named ZBM-H targeted endoplasmic reticulum and induced an intact autophagy flux in lung cancer cells. Furthermore, ZBM-H promoted the binding of GRP78 to AMPK and increased the phosphorylation of AMPK in a dose- and time-dependent manner. GRP78 knockdown inhibited ZBM-H-induced AMPK phosphorylation and ZBM-H-stimulated autophagy. In addition, mass spectrometry combined with point mutation experiments revealed that ZBM-H increased GRP78 activity by inhibiting HOCl-induced lysine 353 oxidation of GRP78. Following ZBM-H treatment in vitro and in vivo, cell growth was significantly inhibited while apoptosis was induced. Nevertheless, exogenous HOCl partially reversed ZBM-H-inhibited cell growth and ZBM-H-induced GRP78 activation. In brief, we found that an endoplasmic reticulum-targeted HOCl probe named ZBM-H, acting through attenuating HOCl-induced GRP78 oxidation, inhibited tumor cell survival by promoting autophagy and apoptosis. Overall, these data demonstrated a novel mechanism of hypochlorous acid regulating autophagy by promoting the oxidation modification of GRP78.


2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i18-i18
Author(s):  
Catherine Delbrouck ◽  
Vitaly I Pozdeev ◽  
Anais Oudin ◽  
Kamil Grzyb ◽  
Laura Neises ◽  
...  

Abstract Serine catabolism via the folate cycle provides formate that is essential for nucleotide synthesis in proliferating cells. In addition to this canonical function to support biomass production in anabolic cells, we have recently demonstrated in vitro and in vivo that formate production in cancer cells is often in excess of the anabolic demand. This excess formate production is characterized by formate overflow and thus, net formate excretion into the tumor microenvironment. Interestingly, we observe increased rates of formate overflow upon different chemical perturbations that induce growth arrest. Thus, stressed cancer cells that encounter growth restriction such as upon chemotherapy, are often characterized by increased formate release rates. We demonstrated that such high formate levels in the extracellular space promote invasion of glioblastoma cells. Using ex vivo brain slice cultures and an orthotopic brain tumor model, we demonstrate that silencing MTHFD1L, the essential enzyme to enable formate overflow, results in decreased invasiveness of the tumor. Embarking from this observation, we investigated the underlying mechanism and now provide evidence that the formate-dependent increase of cell motility is mediated by an activation of Ca2+ signaling. Activation of Ca2+ signaling triggers integrin and matrix metallopeptidase (MMP) responses enabling the invasion process. Targeting either the Ca2+ response or MMP release can suppress the formate dependent increase in invasion. Finally, we tested the effect of formate also in context of breast cancer where we were able to recapitulate our observation of increased invasiveness and, in this case, formate also promoted the metastatic potential. We conclude that excreted formate might serve as a cellular stress signal that represents a promotive trigger to support tumor escape mechanisms.


Author(s):  
Lansheng Zhang ◽  
Xia Zheng ◽  
Anqi Shen ◽  
Daojin Hua ◽  
Panrong Zhu ◽  
...  

Chemoresistance remains a major obstacle for improving the clinical outcome of patients with breast cancer. Recently, long noncoding RNAs (lncRNAs) have been implicated in breast cancer chemoresistance. However, the function and underlying mechanism are still largely unknown. Using lncRNA microarray, we identified 122 upregulated and 475 downregulated lncRNAs that might be related to the breast cancer chemoresistance. Among them, RP11-70C1.3 was one of the most highly expressed lncRNAs. In breast cancer patients, high RP11-70C1.3 expression predicted poor prognosis. Knockdown of RP11-70C1.3 inhibited the multidrug resistance of breast cancer cells in vitro and in vivo. Further investigations revealed that RP11-70C1.3 functioned as a competing endogenous RNA (ceRNA) for miR-6736-3p to increase NRP-1 expression. Notably, the rescue experiments showed that both miR-6736-3p inhibitor and NRP-1 overexpression could partly reverse the suppressive influence of RP11-70C1.3 knockdown on breast cancer chemoresistance. In conclusion, our study indicated that lncRNA RP11-70C1.3 regulated NRP-1 expression by sponging miR-6736-3p to confer chemoresistance of breast cancer cells. RP11-70C1.3 might be a potential therapeutic target in enhancing the clinical efficacy of chemotherapy in breast cancer.


Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1806
Author(s):  
Kwang-Youn Kim ◽  
Un-Jung Yun ◽  
Seung-Hee Yeom ◽  
Sang-Chan Kim ◽  
Hu-Jang Lee ◽  
...  

Chemotherapy is an essential strategy for cancer treatment. On the other hand, consistent exposure to chemotherapeutic drugs induces chemo-resistance in cancer cells through a variety of mechanisms. Therefore, it is important to develop a new drug inhibiting chemo-resistance. Although hemistepsin A (HsA) is known to have anti-tumor effects, the molecular mechanisms of HsA-mediated cell death are unclear. Accordingly, this study examined whether HsA could induce apoptosis in aggressive prostate cancer cells, along with its underlying mechanism. Using HsA on two prostate cancer cell lines, PC-3 and LNCaP cells, the cell analysis and in vivo xenograft model were assayed. In this study, HsA induced apoptosis and autophagy in PC-3 cells. HsA-mediated ROS production attenuated HsA-induced apoptosis and autophagy after treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, autophagy inhibition by 3-MA or CQ is involved in accelerating the apoptosis induced by HsA. Furthermore, we showed the anti-tumor effects of HsA in mice, as assessed by the reduced growth of the xenografted tumors. In conclusion, HsA induced apoptosis and ROS generation, which were blocked by protective autophagy signaling.


2021 ◽  
Author(s):  
Lingmiao Kong ◽  
Fei Xiao ◽  
Yong'gang Wei ◽  
Zhongxue Feng ◽  
Min Li ◽  
...  

Abstract Background Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-associated mortality in women worldwide. Intermedin (IMD) is an endogenous peptide that belongs to the calcitonin gene-related peptide family and has been reported to play important roles in several types of cancers, including breast cancer. In this study, we sought to investigate how IMD affects the behavior of breast cancer cells, the underlying mechanism of these effects, and whether blockade of IMD has a therapeutic effect against breast cancer. Methods Transcriptome sequencing (RNA-Seq), cell biological experiments, Western blotting (WB), immunoprecipitation (IP), and animal tumor models were used. Results IMD expression was significantly increased in breast cancer samples, and the IMD level was positively correlated with lymph node metastasis and Ki67 expression. Cell biological experiments showed that IMD promoted the anchorage-independent growth, migration, and invasive ability of breast cancer cells. Inhibiting IMD activity with an anti-IMD monoclonal antibody blocked these tumor-promoting effects. In addition, blockade of IMD reduced in situ tumor growth and significantly decreased lung metastasis of 4T1 breast cancer in vivo. IMD induced Src kinase phosphorylation, which triggered the transcription of c-Myc, a major oncoprotein controlling the expression of genes that encode ribosomal components. Our data suggest that IMD is involved in breast cancer cell invasion and metastasis, potentially through increasing ribosome biogenesis and protein translation via the Src/c-Myc signaling pathway. Conclusion These results suggest that IMD may be a novel target for the treatment of breast cancer.


2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Jianling Bi ◽  
Shujie Yang ◽  
Long Li ◽  
Qun Dai ◽  
Nicholas Borcherding ◽  
...  

Abstract Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death driven by lipid hydroperoxides within biological membranes. Although therapy-resistant mesenchymal-high cancers are particularly vulnerable to ferroptosis inducers, especially phospholipid glutathione peroxidase 4 (GPx4) inhibitors, the underlying mechanism is yet to be deciphered. As such, the full application of GPx4 inhibitors in cancer therapy remains challenging. Here we demonstrate that metadherin (MTDH) confers a therapy-resistant mesenchymal-high cell state and enhanced sensitivity to inducers of ferroptosis. Mechanistically, MTDH inhibited GPx4, as well as the solute carrier family 3 member 2 (SLC3A2, a system Xc− heterodimerization partner), at both the messenger RNA and protein levels. Our metabolomic studies demonstrated that MTDH reduced intracellular cysteine, but increased glutamate levels, ultimately decreasing levels of glutathione and setting the stage for increased vulnerability to ferroptosis. Finally, we observed an enhanced antitumor effect when we combined various ferroptosis inducers both in vitro and in vivo; the level of MTDH correlated with the ferroptotic effect. We have demonstrated for the first time that MTDH enhances the vulnerability of cancer cells to ferroptosis and may serve as a therapeutic biomarker for future ferroptosis-centered cancer therapy.


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