CTP: Phosphocholine cytidyltransferase alpha (CCTalpha) siRNA induce cell death in p53 negative and positive lung cancer cells

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.

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Momordica charantia L. Induces Non-Apoptotic Cell Death in Human MDA-MB-436 Breast and A549 Lung Cancer Cells by Disrupting Energy Metabolism and Exacerbating Reactive Oxygen Species’ Generation

Journal of Ethnopharmacology ◽

10.1016/j.jep.2021.114036 ◽

2021 ◽

pp. 114036

Author(s):

Adeola Folasade Ehigie ◽

Peng Wei ◽

Taotao Wei ◽

Xiyun Yan ◽

Olufunso O. Olorunsogo ◽

...

Keyword(s):

Lung Cancer ◽

Reactive Oxygen Species ◽

Cell Death ◽

Energy Metabolism ◽

Cancer Cells ◽

Apoptotic Cell ◽

Reactive Oxygen Species Generation ◽

Lung Cancer Cells ◽

Oxygen Species ◽

A549 Lung

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

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2016.03.079 ◽

2016 ◽

Vol 26 (9) ◽

pp. 2119-2123 ◽

Cited By ~ 10

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

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

Cancer Investigation ◽

10.3109/07357907.2014.905585 ◽

2014 ◽

Vol 32 (6) ◽

pp. 209-217 ◽

Cited By ~ 19

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

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

10.20944/preprints202012.0376.v1 ◽

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.

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