title: Near-infrared photothermal therapy using EGFR-targeted gold nanoparticles increases autophagic cell death in breast cancer.
abstract: Although triple negative breast cancer (TNBC) is a small percentage of all breast cancers, to date, TNBC is one of the most challenging types of breast cancer for basic and clinic research because TNBC patients display a high risk of relapse, shorter overall survival and limited therapeutic options after completion of conventional chemotherapy compared with patients with other breast cancer subtypes. The epidermal growth factor receptor (EGFR) is a promising target for TNBC treatment. Although near infrared-photothermal therapy (NIR-PTT) using anti-EGFR antibody-conjugated gold nanorods (anti-EGFR-GNs), has attracted considerable interest for non-invasive and targeted TNBC treatment through an activation of apoptotic pathway, it is unclear whether anti-EGFR-GNs-combined NIR-PTT modulates the induction of autophagy contributing to cell death. Therefore, we investigated the autophagic cell death in cultured TNBC cells and mouse xenograft tumors during anti-EGFR-GNs-combined NIR-PTT. We here found that the cytotoxicity induced by anti-EGFR-GNs-combined NIR-PTT was rescued by treatment with autophagy inhibitor, 3-methyladenine (3-MA). Anti-EGFR-GNs-combined NIR-PTT induced remarkable levels of autophagy activity as evidenced by a large number of autophagic vesicles and a significant increase in autophagy-specific proteins; microtubule-associated protein light chain 3 (LC3), p62, beclin-1, and autophagy-related gene5 (Atg5), accompanying the inhibition of AKT-mTOR signaling pathway responsible for inducing autophagy. Moreover, in mouse xenograft tumors, anti-EGFR-GNs-combined NIR-PTT also increased LC3 and beclin-1 levels. Our findings, for the first time, demonstrate that anti-EGFR-GNs-combined NIR-PTT remarkably induces autophagy leading to EGFR-targeted cancer cell death.
authors.affiliation: Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Radiology, Yanbian University Hospital, 1327 JuZi Street, Yanji City, JiLin Province 133000, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea.
authors.forename: Hoe Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji 133002, China.
authors.forename: Tiefeng
authors.initials: T
authors.lastname: Jin
authors.affiliation: Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea. Electronic address: moonwk@snu.ac.kr.
authors.forename: Woo Kyung
authors.initials: WK
authors.lastname: Moon
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology*; D001343:Autophagy / Q000187:drug effects* / Q000528:radiation effects; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006046:Gold / Q000737:chemistry*; D006801:Humans; D007259:Infrared Rays; D053768:Metal Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010789:Phototherapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: D000906:Antibodies; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; D006046:Gold; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000225:Adenine
keywords: Autophagy; Breast cancer; Epidermal growth factor receptor; Gold nanorod; Photothermal therapy