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. Here, we found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetic or chemical-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 (a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viabilty 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 in hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death; whereas culturing cells in 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.

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

“…As a result, the dramatic induction of profibrotic gene expression observed upon AAN at this time point cannot solely be attributed to Yap overexpression. Although the efficacy of VP treatment to inhibit fibrosis in our KS mouse model seems to suggest that Yap is a key mediator of kidney fibrosis, recent work revealed that VP inhibited Stat3 activation in colon cancer independently of VP's function as a Yap inhibitor (61). This observation brings to light the possibility that VP also inhibits fibrosis via other mechanisms in addition to its role as an inhibitor of Yap activity.…”

YAP promotes erlotinib resistance in human non-small cell lung cancer cells

“…In our study, we verified that verteporfin decreased YAP protein expression, GTIIC reporter activity and mRNA expression of downstream genes AREG and CTGF in H1975 cells. Our results suggest that verteporfin has an effect similar to that of YAP siRNA on inhibiting YAP, and less likely through off-target effects [30]. Verteporfin increased sensitivity of H1975 cells to erlotinib and in combination with erlotinib, synergistically reduced migration, invasion and tumor sphere formation abilities in H1975 cells.…”

YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and Renal Fibrogenesis

“…We show that verteporfin reduces YAP and TAZ mRNA levels, suggesting that decreased synthesis of YAP and TAZ may at least partially explain our findings. However, because recent reports have suggested that verteporfin may also cause protein aggregation through oxidative crosslinking and enhanced degradation, 38,39 other effects of this drug may also play a role.…”

“…Recent reports have also suggested, however, that verteporfin may directly enhance the degradation of certain proteins through oxidative crosslinking and oligomerization. 38,39 Thus, verteporfin may reduce Smad2/3 levels via multiple mechanisms, some of which are likely YAP/TAZ dependent, whereas others may be YAP/TAZ independent.…”