title: A Novel Small-Molecule Inhibitor Targeting CREB-CBP Complex Possesses Anti-Cancer Effects along with Cell Cycle Regulation, Autophagy Suppression and Endoplasmic Reticulum Stress.
abstract: Lung adenocarcinoma, the most common subtype of lung cancer, is the leading cause of cancer death worldwide. Despite attempts for the treatment of lung cancer which have been accumulating, promising new therapies are still needed. Here, we found that cyclic-AMP response element-binding protein (CREB)-CREB binding protein (CBP) transcription factors complex inhibitor, Naphthol AS-TR phosphate (NASTRp), is a potential therapeutic agent for lung cancer. We show that NASTRp inhibited oncogenic cell properties through cell cycle arrest with concomitant suppression of tumor-promoting autophagy with down-regulations of Atg5-12 and Atg7, and accumulation of p62 in human lung cancer cell lines. In addition, NASTRp induced expression of endoplasmic reticulum stress markers such as DDIT3/CHOP, and led to apoptosis along with Bim induction. These findings suggest that transcription factor/co-activator complex, CREB-CBP, can be a potential therapeutic target and its inhibition could be a novel therapeutic strategy for lung cancer.
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06520, United States of America.
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06520, United States of America.
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Park
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06520, United States of America.
authors.forename: Sin-Aye
authors.initials: SA
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Ryu
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, United States of America.
authors.forename: Wuyi
authors.initials: W
authors.lastname: Meng
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06520, United States of America.
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Jürgensmeier
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States of America.
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06520, United States of America.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Boyer
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06520, United States of America; Translational Research Program, Yale Comprehensive Cancer Center, New Haven, CT 06520, United States of America.
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.affiliation: Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, Yale University, New Haven, CT 06520, United States of America; Translational Research Program, Yale Comprehensive Cancer Center, New Haven, CT 06520, United States of America.
authors.forename: Ja Seok
authors.initials: JS
authors.lastname: Koo
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000072224:Bcl-2-Like Protein 11; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D062105:Molecular Docking Simulation; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016016:Proportional Hazards Models; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; D010755:Organophosphates; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D012795:Sialoglycoproteins; C571744:bone sialoprotein (35-62), human; C000606313:naphthol AS-TR phosphate; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes