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: Huabing Zhang, Sadeesh K Ramakrishnan, Daniel Triner, Brook Centofanti, Dhiman Maitra, Balázs Győrffy, Judith S Sebolt-Leopold, Michael K Dame, James Varani, Dean E Brenner, Eric R Fearon, M Bishr Omary, Yatrik M Shah
• Journal: Science signaling (Sci Signal) Vol. 8 Issue 397 Pg. ra98 (Oct 06 2015) ISSN: 1937-9145 [Electronic] United States
• PMID: 26443705 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Neoplasm Proteins
• Phosphoproteins
• Porphyrins
• STAT3 Transcription Factor
• STAT3 protein, human
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Verteporfin
• Acyltransferases
• TAFAZZIN protein, human
• Proteasome Endopeptidase Complex

Topics

• Acyltransferases
• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, physiology)
• Adenocarcinoma (drug therapy, pathology)
• Adenoma (drug therapy, pathology)
• Adenomatous Polyposis Coli (drug therapy, genetics, pathology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (chemically induced, drug therapy, pathology)
• Genes, APC
• HEK293 Cells
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Weight
• Neoplasm Proteins (antagonists & inhibitors, drug effects, physiology)
• Phosphoproteins (antagonists & inhibitors, physiology)
• Phosphorylation
• Porphyrins (pharmacology)
• Proteasome Endopeptidase Complex (drug effects)
• Protein Multimerization (drug effects)
• Protein Processing, Post-Translational
• STAT3 Transcription Factor (antagonists & inhibitors)
• Transcription Factors (antagonists & inhibitors)
• Transcription, Genetic (drug effects)
• Verteporfin
• Xenograft Model Antitumor Assays
• YAP-Signaling Proteins