Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A

Sojka, Damian Robert; Hasterok, Sylwia; Vydra, Natalia; Toma-Jonik, Agnieszka; Wieczorek, Anna; Gogler-Pigłowska, Agnieszka; Ścieglińska, Dorota

doi:10.3390/cells10061418

Cited by 12 publications

(6 citation statements)

References 53 publications

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“…Li et al showed that the cell viability of LNCaP cells is reduced to 20% after treatment with 30 μM Manumycin A ( Li et al, 2014 ). Our findings are in line with that and with that of other studies showing IC 50 values in different cell lines between 4.3 and 50 µM Manumycin A ( She et al, 2005 ; Cho et al, 2015 ; Giudice et al, 2016 ; Kim et al, 2016 ; Sojka et al, 2021 ). Like Li et al, we were not able to induce a complete inhibition of cell growth, even when using concentrations of 100 μM Manumycin A.…”

Section: Discussionsupporting

confidence: 93%

Analyzing the postulated inhibitory effect of Manumycin A on farnesyltransferase

Hagemann

Altrogge²,

Kehrenberg³

et al. 2022

Front. Chem.

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Manumycin A is postulated to be a specific inhibitor against the farnesyltransferase (FTase) since this effect has been shown in 1993 for yeast FTase. Since then, plenty of studies investigated Manumycin A in human cells as well as in model organisms like Caenorhabditis elegans. Some studies pointed to additional targets and pathways involved in Manumycin A effects like apoptosis. Therefore, these studies created doubt whether the main mechanism of action of Manumycin A is FTase inhibition. For some of these alternative targets half maximal inhibitory concentrations (IC50) of Manumycin A are available, but not for human and C. elegans FTase. So, we aimed to 1) characterize missing C. elegans FTase kinetics, 2) elucidate the IC50 and Ki values of Manumycin A on purified human and C. elegans FTase 3) investigate Manumycin A dependent expression of FTase and apoptosis genes in C. elegans. C. elegans FTase has its temperature optimum at 40°C with KM of 1.3 µM (farnesylpyrophosphate) and 1.7 µM (protein derivate). Whilst other targets are inhibitable by Manumycin A at the nanomolar level, we found that Manumycin A inhibits cell-free FTase in micromolar concentrations (Ki human 4.15 μM; KiC. elegans 3.16 μM). Furthermore, our gene expression results correlate with other studies indicating that thioredoxin reductase 1 is the main target of Manumycin A. According to our results, the ability of Manumycin A to inhibit the FTase at the micromolar level is rather neglectable for its cellular effects, so we postulate that the classification as a specific FTase inhibitor is no longer valid.

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Section: Discussionsupporting

confidence: 93%

Analyzing the postulated inhibitory effect of Manumycin A on farnesyltransferase

Hagemann

Altrogge²,

Kehrenberg³

et al. 2022

Front. Chem.

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“…Therefore, our results suggest that increased loading of HSPA2 and HSPA1 into EVs may be a part of non-cell-autonomous mechanisms of proteostasis control upon proteotoxic stress. In this context, our previously published results 33,35 allow to speculate that HSPA paralogs could act in concert due to their high functional redundancy.…”

Section: Discussionmentioning

confidence: 92%

Heat shock protein A2 is a novel extracellular vesicle-associated protein

Sojka

Abramowicz

Adamiec-Organiściok

et al. 2023

Sci Rep

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Abstract70-kDa Heat Shock Proteins (HSPA/HSP70) are chaperones playing a central role in the proteostasis control mechanisms. Their basal expression can be highly elevated as an adaptive response to environmental and pathophysiological stress conditions. HSPA2, one of poorly characterised chaperones of the HSPA/HSP70 family, has recently emerged as epithelial cells differentiation-related factor. It is also commonly expressed in cancer cells, where its functional significance remains unclear. Previously, we have found that proteotoxic stress provokes a decrease in HSPA2 levels in cancer cells. In the present study we found that proteasome inhibition-related loss of HSPA2 from cancer cells neither is related to a block in the gene transcription nor does it relate to increased autophagy-mediated disposals of the protein. Proteotoxic stress stimulated extracellular release of HSPA2 in extracellular vesicles (EVs). Interestingly, EVs containing HSPA2 are also released by non-stressed cancer and normal cells. In human urinary EVs levels of HSPA2 were correlated with the levels of TSG101, one of the main EVs markers. We conclude that HSPA2 may constitute basic components of EVs. Nevertheless, its specific role in EVs and cell-to-cell communication requires further investigation.

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“…The in vitro model also indicated high HSPA6 expression inhibited the proliferation, migration and invasion of TNBC cell lines [ 30 ]. Besides, treating lung cancer cells with Manumycin A induced up-regulation of HSPA6, which could form a positive feedback loop and sensitize cancer cells to Manumycin A treatment [ 31 ]. On the contrast, one of the down-regulated DEGs OPN3 (ranks 16 of most down-regulated list) might be the potential oncogene target.…”

Section: Discussionmentioning

confidence: 99%

Total coumarins of Pileostegia tomentella induces cell death in SCLC by reprogramming metabolic patterns, possibly through attenuating β-catenin/AMPK/SIRT1

Liu

Wu²,

et al. 2023

Chin Med

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Background Small-cell lung cancer (SCLC) is a high malignant and high energy-consuming type of lung cancer. Total coumarins of Pileostegia tomentella (TCPT) from a traditional folk medicine of Yao minority, is a potential anti-cancer mixture against SCLC, but the pharmacological and molecular mechanism of TCPT remains largely unknown. Methods Screening of viability inhibition of TCPT among 7 cell lines were conducted by using CCK-8 assays. Anti-proliferative activities of TCPT in SCLC were observed by using colony formation and flow cytometry assays. Morphological changes were observed by transmission electron microscope and Mito-Tracker staining. High Throughput RNA-seq analysis and bio-informatics analysis were applied to find potential targeted biological and signaling pathways affected by TCPT. The mRNA expression of DEGs and protein expression of signalling proteins and metabolic enzymes were verified by qPCR and Western blot assays. Activity of rate-limiting enzymes and metabolite level were detected by corresponding enzyme activity and metabolites kits. Xenograft nude mice model of SCLC was established to observe the in vivo inhibition, metabolism reprogramming and mechanism of TCPT. Results TCPT treatment shows the best inhibition in SCLC cell line H1688 rather than other 5 lung cancer cell lines. Ultrastructural investigation indicates TCPT induces mitochondria damage such as cytoplasm shrinkage, ridges concentration and early sight of autolysosome, as well as decrease of membrane potential. Results of RNA-seq combined bio-informatics analysis find out changes of metabolism progression affected the most by TCPT in SCLC cells, and these changes might be regulated by β-catenin/AMPK/SIRT1 axis. TCPT might mainly decline the activity and expression of rate-limiting enzymes, OGDH, PDHE1, and LDHA/B to reprogram aerobic oxidation pattern, resulting in reduction of ATP production in SCLC cells. Xenograft nude mice model demonstrates TCPT could induce cell death and inhibit growth in vivo. Assimilate to the results of in vitro model, TCPT reprograms metabolism by decreasing the activity and expression of rate-limiting enzymes (OGDH, PDHE1, and LDHA/B), and attenuates the expression of β-catenin, p-β-catenin, AMPK and SIRT1 accordance with in vitro data. Conclusion Our results demonstrated TCPT induces cell death of SCLC by reprograming metabolic patterns, possibly through attenuating master metabolic pathway axis β-catenin/AMPK/SIRT1.

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Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A

Cited by 12 publications

References 53 publications

Analyzing the postulated inhibitory effect of Manumycin A on farnesyltransferase

Analyzing the postulated inhibitory effect of Manumycin A on farnesyltransferase

Heat shock protein A2 is a novel extracellular vesicle-associated protein

Total coumarins of Pileostegia tomentella induces cell death in SCLC by reprogramming metabolic patterns, possibly through attenuating β-catenin/AMPK/SIRT1

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