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Tumor selective proteotoxicity of verteporfin inhibits colon cancer progression independent of YAP1

ABSTRACT: Verteporfin (VP) inhibts colon cancer growth in vivo and in cell lines by inducing high molecular weight oligomerization of proteins. The antitumor effect of VP is independent of its YAP inhibitor activity. Tumor hypoxia contributes partly to antitumor effect of VP by impairing clearance of VP-induced high molecular weight aggregates.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon Epithelial Cell

DISEASE(S): Colon Cancer

SUBMITTER: Sadeesh Ramakrishnan

LAB HEAD: Yatrik M. Shah

PROVIDER: PXD002793 | Pride | 2015-10-14

REPOSITORIES: Pride

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			Action	DRS
	UM_F_2015_0950.raw	Raw
	UM_F_2015_0950_0956ShahHCT-116.msf	Msf
	UM_F_2015_0950_0956ShahHCT-116.xlsx	Xlsx
	UM_F_2015_0951.raw	Raw
	UM_F_2015_0952.raw	Raw

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Publications

Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1.

Zhang Huabing H Ramakrishnan Sadeesh K SK Triner Daniel D Centofanti Brook B Maitra Dhiman D Győrffy Balázs B Sebolt-Leopold Judith S JS Dame Michael K MK Varani James J Brenner Dean E DE Fearon Eric R ER Omary M Bishr MB Shah Yatrik M YM

Science signaling 20151006 397

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 ...[more]

PMID: 26443705

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Project description: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.

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