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: Kazufumi Ohshiro, Suresh K Rayala, Seiji Kondo, Amitabh Gaur, Ratna K Vadlamudi, Adel K El-Naggar, Rakesh Kumar
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 17 Pg. 8164-71 (Sep 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17804729 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Co-Repressor Proteins
• Endosomal Sorting Complexes Required for Transport
• MAP1LC3A protein, human
• Microtubule-Associated Proteins
• PELP1 protein, human
• Phosphoproteins
• Receptors, Estrogen
• Stilbenes
• Trans-Activators
• Transcription Factors
• hepatocyte growth factor-regulated tyrosine kinase substrate
• Resveratrol

Topics

• Adenocarcinoma (metabolism, pathology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Autophagy (drug effects, physiology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Co-Repressor Proteins
• Endosomal Sorting Complexes Required for Transport
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Lysosomes (drug effects, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Models, Biological
• Phosphoproteins (metabolism)
• Protein Transport (drug effects)
• Receptors, Estrogen (metabolism)
• Resveratrol
• Salivary Gland Neoplasms (genetics, metabolism, pathology)
• Stilbenes (pharmacology)
• Trans-Activators (isolation & purification, metabolism)
• Transcription Factors
• Tumor Cells, Cultured