title: Identifying the estrogen receptor coactivator PELP1 in autophagosomes.
abstract: Resveratrol, a well-established phytoestrogen and chemopreventive agent, has gained much attention among oncologists because it can act as both estrogen receptor agonist and antagonist, depending on dosage and cell context. It is increasingly accepted that steroidal receptor coregulators may also function in the cytoplasmic compartment. Deregulation and altered localization of these coregulators could influence target gene expression and participate in the development of hormone-responsive cancers. Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1), a novel estrogen receptor (ER) coactivator, plays an important role in the genomic and nongenomic actions of ER. Furthermore, recent studies have shown that differential compartmentalization of PELP1 could be crucial in modulating sensitivity to tamoxifen. In this study, we investigated the role of PELP1 in resveratrol-induced autophagy in lung cancer and salivary gland adenocarcinoma cell lines. Resveratrol reversibly inhibited the growth of these cancer cell lines and induced autophagy, as evidenced by microtubule-associated protein 1 light chain 3 (LC3) up-regulation in a time-dependent and 3-methyladenine-sensitive manner. Confocal microscopic analysis showed that resveratrol induced PELP1 accumulation in autophagosomes with green fluorescent protein-LC3. The intermediary molecule involved in PELP1 accumulation in resveratrol-induced autophagosomes is hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a trafficking molecule that binds to PELP1. These results identify PELP1 for the first time in autophagosomes, implying that both PELP1 and HRS reallocate to autophagosomes in response to resveratrol treatment, which might be important in the process of autophagy in the cancer cells.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Rayala
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Amitabh
authors.initials: A
authors.lastname: Gaur
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism*; D000077185:Resveratrol; D012468:Salivary Gland Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology*; D015534:Trans-Activators / Q000302:isolation & purification / Q000378:metabolism*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured