Identification of Cytoskeleton-Associated Proteins Essential for Lysosomal Stability and Survival of Human Cancer Cells

Groth‐Pedersen, Line; Aits, Sonja; Corcelle-Termeau, Elisabeth; Petersen, Nikolaj H.T.; Nylandsted, Jesper; Jäättelä, Marja

doi:10.1371/journal.pone.0045381

Cited by 68 publications

(52 citation statements)

References 52 publications

(82 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The effectiveness of paclitaxel in the treatment of many human cancers has been proven [20, 21]. TPM2, a cytoskeleton-associated protein, appears to be associated with sensitivity to cisplatin in the breast cancer cell line MCF7 [22]; nonetheless, the influence of TPM2 on paclitaxel remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer

Zhang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Tropomyosin-2 (TPM2) plays important roles in functions of the cytoskeleton, such as cytokinesis, vesicle transport, cell proliferation, migration and apoptosis,and these functions imply that TPM2 also plays a role in cancer development. Indeed, it has been shown that TPM2 plays a critical role in some cancers. However, the role of TPM2 in breast cancer is still poorly characterized. Thus, we explored the role of TPM2 in breast cancer. Methods: We analysed TPM2 expression and its correlation with the clinicopathological features in breast cancer. Then, we examined the influence of hypoxia on TPM2 expression and methylation status using bisulfite sequencing PCR. Furthermore, we performed TPM2-mediated migration and invasion assays in the context of hypoxia and examined changes in matrix metalloproteinase-2 (MMP2) expression. Finally, we detected the influence of TPM2 on survival and chemotherapy drug sensitivity. Results: We found that TPM2 expression is down-regulated in breast cancer cells compared to that in normal breast cells. The data from TCGA supported these results. Promoter methylation of TPM2, which could be induced by hypoxia, was responsible for its low expression. Hypoxia might regulate cell invasiveness partly by TPM2 down-regulation-mediated changes of MMP2 expression. Importantly, low TPM2 expression was correlated with lymph node metastasis (P=0.031), tumour node metastasis stage (P=0.01), histological grade (P=0.037), and shorter overall survival (P=0.028). Univariate and multivariate analyses indicated that TPM2 was an independent predictor in breast cancer patients. Paclitaxel chemotherapy did not benefit patients with low TPM2 expression (P<0.0001). TPM2 knockdown significantly reduced cell sensitivity to paclitaxel. Conclusion: TPM2 is a potential novel tumour suppressor gene in breast cancer. TPM2 is associated with poor survival and chemoresistance to paclitaxel in breast cancer, and TPM2 may represent a promising therapeutic gene target for breast cancer patients with chemoresistance.

show abstract

Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer

Zhang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…MYO1G (3 sites), or unconventional myosin IG, is a plasma-membrane associated class 1 myosin and is found in abundance in lymphocytes [45]. It has been found to be related to cell death and a potential factor in cancer [46]. HIVEP3 (2 sites) was found to be the gene with the most strongly associated CpG site (by p-value) in the meta-analysis of Joehanes et al [12], where they note its role in bone formation.…”

Section: Discussionmentioning

confidence: 99%

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers

et al. 2017

View full text Add to dashboard Cite

Background: The evidence for epigenome-wide associations between smoking and DNA methylation continues to grow through cross-sectional studies. However, few large-scale investigations have explored the associations using observations for individuals at multiple time-points. Here, through the use of the Illumina 450K BeadChip and data collected at two time-points separated by approximately 7 years, we investigate changes in methylation over time associated with quitting smoking or remaining a former smoker, and those associated with continued smoking. Results: Our results indicate that after quitting smoking the most rapid reversion of altered methylation occurs within the first two decades, with reversion rates related to the initial differences in methylation. For 52 CpG sites, the change in methylation from baseline to follow-up is significantly different for former smokers relative to the change for never smokers (lowest p-value 3.61 x 10 -39 for cg26703534, gene AHRR). Most of these sites' respective regions have been previously implicated in smoking-associated diseases. Despite the early rapid change, dynamism of methylation appears greater in former smokers vs never smokers even four decades after cessation. Furthermore, our study reveals the heterogeneous effect of continued smoking: the methylation levels of some loci further diverge between smokers and non-smokers, while others re-approach. Though intensity of smoking habit appears more significant than duration, results remain inconclusive. Conclusions: This study improves the understanding of the dynamic link between cigarette smoking and methylation, revealing the continued fluctuation of methylation levels decades after smoking cessation and demonstrating that continuing smoking can have an array of effects. The results can facilitate insights into the molecular mechanisms behind smoking-induced disturbed methylation, improving the possibility for development of biomarkers of past smoking behavior and increasing the understanding of the molecular path from exposure to disease.

show abstract

“…Furthermore, sensitization to LMP upon oncogene-driven transformation and several models of LCD (e.g. mammary gland involution and death induced by cytoskeletal disruption) are associated with increased cysteine cathepsin activity Kreuzaler et al, 2011;Groth-Pedersen et al, 2007;Groth-Pedersen et al, 2012). The LMPpromoting effect of cysteine cathepsins might be due to the intralysosomal degradation of highly glycosylated lysosome-associated membrane proteins, which form a protective glycocalyx shield on the inner lysosomal membrane (Eskelinen et al, 2003;Fehrenbacher et al, 2008).…”

Section: Proteasesmentioning

confidence: 99%

Lysosomal cell death at a glance

Aits

Jäättelä

2013

Journal of Cell Science

Self Cite

517

453

View full text Add to dashboard Cite

Summary Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called “lysosomal cell death”. This form of cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream mechanisms that lead to lysosomal membrane permeabilization.

show abstract

Identification of Cytoskeleton-Associated Proteins Essential for Lysosomal Stability and Survival of Human Cancer Cells

Cited by 68 publications

References 52 publications

Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer

Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers

Lysosomal cell death at a glance

Contact Info

Product

Resources

About