A cell membrane vehicle co-delivering sorafenib and doxorubicin remodel the tumor microenvironment and enhance immunotherapy by inducing immunogenic cell death in lung cancer cells

2020 ◽  
Vol 8 (34) ◽  
pp. 7755-7765 ◽  
Author(s):  
Jun Wan ◽  
Jian Wang ◽  
Min Zhou ◽  
Zhanpeng Rao ◽  
Xiean Ling
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Cancer Therapy ◽  
Cell Membrane ◽  
Cancer Cells ◽  
Cancer Immunotherapy ◽  
Lung Cancer Cells ◽  
Immunogenic Cell Death ◽  
A Cell

Cancer immunotherapy is a promising approach for cancer therapy but is usually hindered by the inhibition of the tumor microenvironment (TME).

scholarly journals Nuclear Transglutaminase 2 interacts with topoisomerase II⍺ to promote DNA damage repair in lung cancer cells

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Xiao Lei ◽  
Kun Cao ◽  
Yuanyuan Chen ◽  
Hui Shen ◽  
Zhe Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Protein Localization ◽  
Transglutaminase 2 ◽  
Lung Cancer Cells ◽  
Mass Spectrometry Analysis ◽  
Cancer Resistance ◽  
Dsb Repair

Abstract Background To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex. Methods A bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo. Results After DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers. Conclusions These findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

Tumor Microenvironment-Triggered In-Situ Cancer Vaccines with Dual Immunogenic Cell Death Inductions for Elevated Antitumor and Antimetastatic Therapy

Nanoscale ◽  
2021 ◽  
Author(s):  
Jun Lin ◽  
Binbin Ding ◽  
Pan Zheng ◽  
Dong Li ◽  
Meifang Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Cancer Vaccines ◽  
High Specificity ◽  
The Body ◽  
Immunogenic Cell Death ◽  
Specific Antigens

Cancer vaccine is to make tumor-specific antigens into vaccines, which then are injected back into the body to activate immune responses for cancer immunotherapy. Despite the high specificity and therapeutic...

scholarly journals Tubulin acetylation enhances lung cancer resistance to paclitaxel-induced cell death through Mcl-1 stabilization

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Onsurang Wattanathamsan ◽  
Rawikorn Thararattanobon ◽  
Ratchanee Rodsiri ◽  
Pithi Chanvorachote ◽  
Chanida Vinayanuwattikun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Trichostatin A ◽  
Primary Lung Cancer ◽  
Lung Cancer Cells ◽  
Cancer Resistance ◽  
Apoptosis Resistance ◽  
Tubulin Acetylation ◽  
Cancer Aggressiveness

AbstractThe posttranslational modifications (PTMs) of microtubules have been reported to play an important role in cancer aggressiveness, including apoptosis resistance. In this study, we aimed to investigate the biological role of microtubule PTMs in the regulation of paclitaxel responsiveness. The acetylated tubulin (Ace-tub) level was strongly associated with paclitaxel sensitivity, as observed in patient-derived primary lung cancer cells and xenografted immunodeficient mice. We showed that paclitaxel-resistant H460 lung cancer cells, generated by a stepwise increase in paclitaxel, exhibited markedly increased tubulin acetylation and consequently acquired paclitaxel resistance. Upregulation of tubulin acetylation by overexpression of α-tubulin acetyltransferase 1 wild-type (αTAT1wt), an enzyme required for acetylation, or by treatment with trichostatin A (TSA), a histone deacetylase 6 (HDAC6) inhibitor, significantly attenuated paclitaxel-induced apoptosis. Investigation of the underlying mechanism revealed that the levels of antiapoptotic Mcl-1 appeared to increase in αTAT1wt-overexpressing and TSA-treated cells compared to control cells, whereas the levels of other antiapoptotic regulatory proteins were unchanged. On the other hand, decreased tubulin acetylation by αTAT1 RNA interference downregulated Mcl-1 expression in patient-derived primary lung cancer and paclitaxel-resistant lung cancer cells. A microtubule sedimentation assay demonstrated that Mcl-1 binds to microtubules preferentially at Ace-type, which prolongs the Mcl-1 half-life (T1/2). Furthermore, immunoprecipitation analysis revealed that polyubiquitination of Mcl-1 was extensively decreased in response to TSA treatment. These data indicate that tubulin acetylation enhances the resistance to paclitaxel-induced cell death by stabilizing Mcl-1 and protecting it from ubiquitin–proteasome-mediated degradation.

A synthetic 2,3-diarylindole induces cell death via apoptosis and autophagy in A549 lung cancer cells

2016 ◽  
Vol 26 (9) ◽  
pp. 2119-2123 ◽  
Author(s):  
Thanya Rukkijakan ◽  
Lukana Ngiwsara ◽  
Kriengsak Lirdprapamongkol ◽  
Jisnuson Svasti ◽  
Nared Phetrak ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
A549 Lung

Biological Effects of125I Seeds Radiation on A549 Lung Cancer Cells: G2/M Arrest and Enhanced Cell Death

2014 ◽  
Vol 32 (6) ◽  
pp. 209-217 ◽  
Author(s):  
Ang Qu ◽  
Hao Wang ◽  
Jinna Li ◽  
Junjie Wang ◽  
Jingjia Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Biological Effects ◽  
Lung Cancer Cells ◽  
A549 Lung

scholarly journals Antidepressant Drug Enhanced Trail Receptor-2 Expression and Sensitized Lung Cancer Cells to Trail-Induced Apoptosis via Inhibition of Autophagic Flux

2020 ◽  
Author(s):  
K.M.A. Zinnah ◽  
Jae-Won Seol ◽  
Sang-Youel Park
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Antidepressant Drug ◽  
Lung Cancer Cells ◽  
Autophagic Flux ◽  
Trail Receptor ◽  
Treatment Needs ◽  
Induced Apoptosis ◽  
Autophagy Inhibition

Autophagy, an alternative cell death mechanism, is also termed programmed cell death type II. Autophagy in cancer treatment needs to be regulated. In our study, autophagy inhibition by desipramine or the autophagy inhibitor chloroquine (CQ) enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 [death receptor (DR5)] expression and subsequently TRAIL-induced apoptosis in TRAIL-resistant A549 lung cancer cells. Genetic inhibition of DR5 substantially reduced desipramine-enhanced TRAIL-mediated apoptosis, proving that DR5 was required to increase TRAIL sensitivity in TRAIL-resistant cancer cells. Desipramine treatment upregulated p62 expression and promoted conversion of light chain 3 (LC3)-I to its lipid-conjugated form, LC3-II, indicating that autophagy inhibition occurred at the final stages of autophagic flux. Transmission electron microscopy analysis showed the presence of condensed autophagosomes, which resulted from the late stages of autophagy inhibition by desipramine. TRAIL, in combination with desipramine or CQ, augmented the expression of apoptosis-related proteins cleaved caspase-8 and cleaved caspase-3. Our results contributed to the understanding of the mechanism underlying the synergistic anti-cancer effect of desipramine and TRAIL and presented a novel mechanism of DR5 upregulation. These findings demonstrated that autophagic flux inhibition by desipramine potentiated TRAIL-induced apoptosis, suggesting that appropriate regulation of autophagy is required for sensitizing TRAIL-resistant cancer cells to TRAIL-mediated apoptosis.

scholarly journals ELF3 Is a Target That Promotes Therapeutic Efficiency in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer Cells via Inhibiting PKCί

2021 ◽  
Vol 22 (22) ◽  
pp. 12287
Author(s):  
Jeon-Soo Lee ◽  
Young Eun Choi ◽  
Sunshin Kim ◽  
Ji-Youn Han ◽  
Sung-Ho Goh
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Therapeutic Effects ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tki

(1) Background: Mutations in epidermal growth factor receptor (EGFR) proteins account for many non-small cell lung cancers (NSCLCs), and EGFR tyrosine kinase inhibitors (TKIs) are being used as targeted therapeutics. However, resistance to TKIs continues to increase owing to additional mutations in more than half of the patients receiving EGFR TKI therapy. In addition to targeting new mutations with next-generation therapeutics, it is necessary to find an alternative target to overcome the challenges associated with resistance. (2) Methods: To identify potential alternative targets in patients with NSCLC undergoing targeted therapy, putative targets were identified by transcriptome profiling and validated for their biological and therapeutic effects in vitro and in vivo. (3) Results: ELF3 was found to be differentially expressed in NSCLC, and ELF3 knockdown significantly increased cell death in K-Ras mutant as well as in EGFR L858R/T790M mutation harboring lung cancer cells. We also found that auranofin, an inhibitor of protein kinase C iota (PKCί), a protein upstream of ELF3, effectively induced cell death. (4) Conclusions: Our study suggests that blocking ELF3 is an effective way to induce cell death in NSCLC with K-Ras and EGFR T790M/L858R mutations and thus advocates the use of auranofin as an effective alternative drug to overcome EGFR TKI resistance.

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