title: Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1.
abstract: Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1 activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. We found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetically or chemically induced mouse models of CRC, in patient-derived xenografts, and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high-molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (signal transducer and activator of transcription 3; a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viability of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells under hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death, whereas culturing cells under normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Huabing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Triner
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Brook
authors.initials: B
authors.lastname: Centofanti
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Dhiman
authors.initials: D
authors.lastname: Maitra
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, MTA-SE Pediatrics and Nephrology Research Group, Semmelweis University 2nd Department of Pediatrics, Budapest H-1117, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Sebolt-Leopold
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Dame
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: James
authors.initials: J
authors.lastname: Varani
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Dean E
authors.initials: DE
authors.lastname: Brenner
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Veterans Affairs Ann Arbor Health Care System, Ann Arbor, MI 48105, USA.
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. shahy@umich.edu.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000502:physiology; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000236:Adenoma / Q000188:drug therapy* / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017491:Genes, APC; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000502:physiology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010766:Phosphorylation; D011166:Porphyrins / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D000077362:Verteporfin; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011166:Porphyrins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000077362:Verteporfin; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D046988:Proteasome Endopeptidase Complex