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 6

Inhibition of PDE5 potentiates 67LR-dependent cell death by enhancing the 67LR-dependent signaling pathway in MM cells.

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Inhibition of PDE5 potentiates 67LR-dependent cell death by enhancing th...
(A) U266 cells were preincubated for 3 hours with anti-67LR antibody or IgM control antibody, then treated or not for 96 hours with 5 μM EGCG and/or vardenafil. Apoptotic cells were double stained with annexin V–Alexa Fluor 488 and PI and analyzed by flow cytometry. (B) Cells were pretreated or not with 5 μM vardenafil and cultured for 3 hours in the presence or absence of 5 μM EGCG, followed by measurement of the amount of cGMP in the cells. (C) U266 cells were treated or not for 96 hours with the sGC activator BAY 41-2272 (1 μM) in the presence or absence of 5 μM vardenafil. (D) U266 cells were preincubated or not for 3 hours with the ASM-specific inhibitor desipramine (Des; 5 μM), then treated or not for 96 hours with 5 μM EGCG and/or vardenafil. (E) Sensitivity of U266 cells to EGCG and/or vardenafil (5 μM for 96 hours) after ASM knockdown. n = 3 per group. All data are mean ± SEM. (F) The combination of EGCG as a cancer-specific cGMP inducer with an inhibitor targeting cancer-overexpressed PDE5 could be a useful strategy for cancer-selective chemotherapy. Left: In the absence of PDE5 inhibitor, overexpressed PDE5 in cancer attenuates the anticancer effect of EGCG. Right: PDE5 inhibition potentiates the anticancer effect of EGCG.