Impairment of Nucleolin Activity and Phosphorylation by a Trachylobane Diterpene from Psiadia punctulata in Cancer Cells
Human nucleolin (hNcl) is a multifunctional protein involved in the progression of various cancers and plays a key role in other pathologies. Therefore, there is still unsatisfied demand for hNcl modulators. Recently, we demonstrated that the plant ent-kaurane diterpene oridonin inhibits hNcl but, unfortunately, this compound is quite toxic for healthy cells. Trachylobane diterpene 6,19-dihydroxy-ent-trachiloban-17-oic acid (compound 12) extracted from Psiadia punctulata (DC.) Vatke (Asteraceae) emerged as a ligand of hNcl from a cellular thermal shift assay (CETSA)-based screening of a small library of diterpenes. Effective interaction between this compound and the protein was demonstrated to occur both in vitro and inside two different types of cancer cells. Based on the experimental and computational data, a model of the hNcl/compound 12 complex was built. Because of this binding, hNcl mRNA chaperone activity was significantly reduced, and the level of phosphorylation of the protein was affected. At the biological level, cancer cell incubation with compound 12 produced a cell cycle block in the subG0/G1 phase and induced early apoptosis, whereas no cytotoxicity towards healthy cells was observed. Overall, these results suggested that 6,19-dihydroxy-ent-trachiloban-17-oic could represent a selective antitumoral agent and a promising lead for designing innovative hNcl inhibitors also usable for therapeutic purposes.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
|---|---|
| Enthalten in: |
International journal of molecular sciences - 23(2022), 19 vom: 27. Sept. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bellone, Maria Laura [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 17.10.2022 Date Revised 13.12.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3390/ijms231911390 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM347477542 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM347477542 | ||
| 003 | DE-627 | ||
| 005 | 20231227130945.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/ijms231911390 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1225.xml |
| 035 | |a (DE-627)NLM347477542 | ||
| 035 | |a (NLM)36232690 | ||
| 035 | |a (PII)11390 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bellone, Maria Laura |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Impairment of Nucleolin Activity and Phosphorylation by a Trachylobane Diterpene from Psiadia punctulata in Cancer Cells |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 17.10.2022 | ||
| 500 | |a Date Revised 13.12.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Human nucleolin (hNcl) is a multifunctional protein involved in the progression of various cancers and plays a key role in other pathologies. Therefore, there is still unsatisfied demand for hNcl modulators. Recently, we demonstrated that the plant ent-kaurane diterpene oridonin inhibits hNcl but, unfortunately, this compound is quite toxic for healthy cells. Trachylobane diterpene 6,19-dihydroxy-ent-trachiloban-17-oic acid (compound 12) extracted from Psiadia punctulata (DC.) Vatke (Asteraceae) emerged as a ligand of hNcl from a cellular thermal shift assay (CETSA)-based screening of a small library of diterpenes. Effective interaction between this compound and the protein was demonstrated to occur both in vitro and inside two different types of cancer cells. Based on the experimental and computational data, a model of the hNcl/compound 12 complex was built. Because of this binding, hNcl mRNA chaperone activity was significantly reduced, and the level of phosphorylation of the protein was affected. At the biological level, cancer cell incubation with compound 12 produced a cell cycle block in the subG0/G1 phase and induced early apoptosis, whereas no cytotoxicity towards healthy cells was observed. Overall, these results suggested that 6,19-dihydroxy-ent-trachiloban-17-oic could represent a selective antitumoral agent and a promising lead for designing innovative hNcl inhibitors also usable for therapeutic purposes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a cancer cell apoptosis | |
| 650 | 4 | |a nucleolin | |
| 650 | 4 | |a plant diterpenes | |
| 650 | 4 | |a post-translational modification | |
| 650 | 4 | |a protein–drug interaction | |
| 650 | 7 | |a Diterpenes |2 NLM | |
| 650 | 7 | |a Diterpenes, Kaurane |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Phosphoproteins |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a RNA-Binding Proteins |2 NLM | |
| 700 | 1 | |a Fiengo, Lorenzo |e verfasserin |4 aut | |
| 700 | 1 | |a Cerchia, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Cotugno, Roberta |e verfasserin |4 aut | |
| 700 | 1 | |a Bader, Ammar |e verfasserin |4 aut | |
| 700 | 1 | |a Lavecchia, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a De Tommasi, Nunziatina |e verfasserin |4 aut | |
| 700 | 1 | |a Piaz, Fabrizio Dal |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International journal of molecular sciences |d 2008 |g 23(2022), 19 vom: 27. Sept. |w (DE-627)NLM185552161 |x 1422-0067 |7 nnns |
| 773 | 1 | 8 | |g volume:23 |g year:2022 |g number:19 |g day:27 |g month:09 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ijms231911390 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 23 |j 2022 |e 19 |b 27 |c 09 | ||