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PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer.

التفاصيل البيبلوغرافية
العنوان: PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer.
المؤلفون: Salvi A; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA., Young AN; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA., Huntsman AC; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA., Pergande MR; Department of Chemistry, University of Illinois at Chicago, Chicago, IL, 60607, USA., Korkmaz MA; Department of Chemistry, University of Illinois at Chicago, Chicago, IL, 60607, USA., Rathnayake RA; Department of Chemistry, University of Illinois at Chicago, Chicago, IL, 60607, USA., Mize BK; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA., Kinghorn AD; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA., Zhang X; Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA., Ratia K; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA., Schirle M; Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA., Thomas JR; Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA., Brittain SM; Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA., Shelton C; Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, MA, 02139, USA., Aldrich LN; Department of Chemistry, University of Illinois at Chicago, Chicago, IL, 60607, USA., Cologna SM; Department of Chemistry, University of Illinois at Chicago, Chicago, IL, 60607, USA., Fuchs JR; Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA., Burdette JE; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60607, USA. joannab@uic.edu.
المصدر: Cell death & disease [Cell Death Dis] 2022 Jan 10; Vol. 13 (1), pp. 45. Date of Electronic Publication: 2022 Jan 10.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Pub. Group
مواضيع طبية MeSH: Antineoplastic Agents/*pharmacology , Autophagy/*drug effects , Cell Nucleus/*metabolism , Cellular Apoptosis Susceptibility Protein/*metabolism , Cystadenocarcinoma, Serous/*metabolism , Ovarian Neoplasms/*metabolism , Proton-Translocating ATPases/*antagonists & inhibitors, Active Transport, Cell Nucleus/drug effects ; Antineoplastic Agents/metabolism ; Apoptosis/drug effects ; Cell Line, Tumor ; Cellular Apoptosis Susceptibility Protein/genetics ; Cystadenocarcinoma, Serous/drug therapy ; Cystadenocarcinoma, Serous/pathology ; Female ; Humans ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/pathology ; Phyllanthus/chemistry ; Prognosis
مستخلص: PHY34 is a synthetic small molecule, inspired by a compound naturally occurring in tropical plants of the Phyllanthus genus. PHY34 was developed to have potent in vitro and in vivo anticancer activity against high grade serous ovarian cancer (HGSOC) cells. Mechanistically, PHY34 induced apoptosis in ovarian cancer cells by late-stage autophagy inhibition. Furthermore, PHY34 significantly reduced tumor burden in a xenograft model of ovarian cancer. In order to identify its molecular target/s, we undertook an unbiased approach utilizing mass spectrometry-based chemoproteomics. Protein targets from the nucleocytoplasmic transport pathway were identified from the pulldown assay with the cellular apoptosis susceptibility (CAS) protein, also known as CSE1L, representing a likely candidate protein. A tumor microarray confirmed data from mRNA expression data in public databases that CAS expression was elevated in HGSOC and correlated with worse clinical outcomes. Overexpression of CAS reduced PHY34 induced apoptosis in ovarian cancer cells based on PARP cleavage and Annexin V staining. Compounds with a diphyllin structure similar to PHY34 have been shown to inhibit the ATP6V0A2 subunit of V(vacuolar)-ATPase. Therefore, ATP6V0A2 wild-type and ATP6V0A2 V823 mutant cell lines were tested with PHY34, and it was able to induce cell death in the wild-type at 246 pM while the mutant cells were resistant up to 55.46 nM. Overall, our data demonstrate that PHY34 is a promising small molecule for cancer therapy that targets the ATP6V0A2 subunit to induce autophagy inhibition while interacting with CAS and altering nuclear localization of proteins.
(© 2022. The Author(s).)
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معلومات مُعتمدة: F30 CA217079 United States CA NCI NIH HHS; P01 CA125066 United States CA NCI NIH HHS; P01CA125066 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI); 1F30CA217079 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
المشرفين على المادة: 0 (ATP6V0A2 protein, human)
0 (Antineoplastic Agents)
0 (Cellular Apoptosis Susceptibility Protein)
EC 3.6.3.14 (Proton-Translocating ATPases)
تواريخ الأحداث: Date Created: 20220111 Date Completed: 20220325 Latest Revision: 20230917
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC8748433
DOI: 10.1038/s41419-021-04495-w
PMID: 35013112
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-4889
DOI:10.1038/s41419-021-04495-w