Research ArticleCancer

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

Sci. Signal.  06 Oct 2015:
Vol. 8, Issue 397, pp. ra98
DOI: 10.1126/scisignal.aac5418

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Aggregates kill cancer cells

The drug verteporfin is used clinically to enhance phototherapy and may also inhibit the transcription factor YAP1, which is often active in cancers. However, Zhang et al. found a different path to toxicity for verteporfin-mediated death of colorectal cancer cells. Verteporfin triggered the accumulation of toxic amounts of protein oligomers that selectively killed colorectal cancer cells in mice and in cells cultured under hypoxic and nutrient-deprived conditions. Normal cells in culture and in tumor-adjacent tissue sections from mice cleared these aggregates through autophagy and survived. Thus, verteporfin produces tumor-selective proteotoxicity, which may be a useful therapeutic for patients with solid tumors.

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.

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