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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 PKC?/acid sphingomyelinase (PKC?/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.

SUBMITTER: Kumazoe M 

PROVIDER: S-EPMC3561824 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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

Kumazoe Motofumi M   Sugihara Kaori K   Tsukamoto Shuntaro S   Huang Yuhui Y   Tsurudome Yukari Y   Suzuki Takashi T   Suemasu Yumi Y   Ueda Naoki N   Yamashita Shuya S   Kim Yoonhee Y   Yamada Koji K   Tachibana Hirofumi H  

The Journal of clinical investigation 20130125 2


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)  ...[more]

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