ArticleCell death & disease2022
PHY34 inhibits autophagy through V-ATPase V0A2 subunit inhibition and CAS/CSE1L nuclear cargo trafficking in high grade serous ovarian cancer.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Bioactivities and Mechanisms of Action of Diphyllin and Its Derivatives: A Comprehensive Systematic Review.Molecules (Basel, Switzerland) · 2023Pooled it
- Single-cell transcriptomics of chicken ovarian cancer identifying immune subsets with prognostic implications.Poultry science · 2026Article
- Targeting endolysosomal acidification inhibits poxvirus entry and replication.Cell communication and signaling : CCS · 2026Article
- CLC3 regulates V-ATPase to enhance lysosomal degradation and cisplatin resistance in cervical cancer cells.Cell death discovery · 2025Article
- A nitrogen-containing diphyllin derivative C156-P1 exhibited broad-spectrum antiviral activity againstAntimicrobial agents and chemotherapy · 2025Article
- Proteomic Landscapes of 3D and 2D Models of High-Grade Serous Ovarian Carcinoma: Implications for Carboplatin Response.Journal of proteome research · 2025Article
- Prolactin Regulates Seasonal Changes in Renal Rheostasis in Djungarian Hamsters.Endocrinology · 2025Article
- Antitumor and immunomodulatory activities of diphyllin and its derivatives.Bioorganic & medicinal chemistry · 2025Review
- Article
- MIR937 amplification potentiates ovarian cancer progression by attenuating FBXO16 inhibition on ULK1-mediated autophagy.Cell death & disease · 2024Article
- Evaluation of potency and metabolic stability of diphyllin-derived Vacuolar-ATPase inhibitors.European journal of medicinal chemistry · 2024Article
- Chromosome Segregation-1-like Gene Participates in Ferroptosis in Human Ovarian Granulosa Cells via Nucleocytoplasmic Transport.Antioxidants (Basel, Switzerland) · 2024Article
- Epirubicin induces cardiotoxicity through disrupting ATP6V0A2-dependent lysosomal acidification and triggering ferroptosis in cardiomyocytes.Cell death discovery · 2024Article
- Natural products as inhibitors against pancreatic cancer cell proliferation and invasion: possible mechanisms.American journal of cancer research · 2024Review
- The interplay between autophagy and cGAS-STING signaling and its implications for cancer.Frontiers in immunology · 2024Review
- Integrated bioinformatics analysis of differentially expressed genes in the temporomandibular joint internal derangement.Clinical and experimental dental research · 2023Article
- Discovery and development of botanical natural products and their analogues as therapeutics for ovarian cancer.Natural product reports · 2023Review
- Role of autophagy and its regulation by noncoding RNAs in ovarian cancer.Experimental biology and medicine (Maywood, N.J.) · 2023Review
- Autophagic mechanisms in longevity intervention: role of natural active compounds.Expert reviews in molecular medicine · 2023Review
- Discovery of Anticancer Agents of Diverse Natural Origin.Journal of natural products · 2022Article
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18 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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