Identifying the estrogen receptor coactivator PELP1 in autophagosomes

Resveratrol, a well-established phytoestrogen and chemo-preventive 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 PELPI could be crucial in modulating sensitivity to tamoxifen. In this study, we investigated the role of PELPI 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 I light chain 3 (LC3) up-regulation in a time-dependent and 3-methyladenine-sensitive manner. Confocal microscopic analysis showed that resveratrol induced PELPI accumulation in autophagosomes with green fluorescent protein-LC3. The intermediary molecule involved in PELPI accumulation in resveratrol-induced autophagosomes is hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a trafficking molecule that binds to PELPI. These results identify PELPI for the first time in autophagosomes, implying that both PELPI and HRS reallocate to autophagosomes in response to resveratrol treatment, which might be important in the process of autophagy in the cancer cells.