67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis
Motofumi Kumazoe, … , Koji Yamada, Hirofumi Tachibana
Motofumi Kumazoe, … , Koji Yamada, Hirofumi Tachibana
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):787-799. https://doi.org/10.1172/JCI64768.
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Research Article

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis

Abstract

The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (–)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.

Authors

Motofumi Kumazoe, Kaori Sugihara, Shuntaro Tsukamoto, Yuhui Huang, Yukari Tsurudome, Takashi Suzuki, Yumi Suemasu, Naoki Ueda, Shuya Yamashita, Yoonhee Kim, Koji Yamada, Hirofumi Tachibana

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Figure 4

Effect of EGCG and a PDE5 inhibitor in combination on myeloma cell proliferation in vivo.

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Effect of EGCG and a PDE5 inhibitor in combination on myeloma cell proli...
(A) Anti-MM effect of EGCG (5 μM) and vardenafil (5 μM) in combination and of lenalidomide for 96 hours in vitro (n = 3). (B) Mouse myeloma MPC-11 cells were pretreated or not with 5 μM vardenafil for 3 hours and cultured in the presence or absence of 5 μM EGCG for 96 hours (n = 3). (C–E) MPC-11 cells were injected subcutaneously into female BALB/c mice, and mice (n = 5 per group) were given single i.p. injections of EGCG (15 mg/kg) and/or vardenafil (5 mg/kg). (C) After 6 hours, tumors were excised and evaluated for phosphorylation of PKCδ at Ser662 (corresponding to human p-PKCδSer664). Original magnification, ×60. (D) ASM activation, assessed by TLC analyses. (E) Cleaved caspase-3 was evaluated by immunofluorescence analyses. Original magnification, ×60. (F and G) MPC-11 cells were injected subcutaneously into female BALB/c mice, and mice (n = 10 per group) were given i.p. injections of EGCG (15 mg/kg) and/or vardenafil (5 mg/kg) every 2 days. Statistical analyses of survival curves were undertaken using log-rank analyses of the Kaplan-Meier curves. All data are mean ± SEM.