Abstract
The anti-apoptotic nature of cancer cells often impedes the effects of anti-cancer therapeutic agents. Multiple death signals influence mitochondria during apoptosis, and though many studies have attempted to elucidate these complicated pathways, Bax oligomerization, an important step in the process, remains controversial. Here we demonstrate that pleckstrin-homology N1 (PLEKHN1), also known as cardiolipin phosphatidic acid binding protein, plays pro-apoptotic roles during reactive oxygen species (ROS)–induced apoptosis. Human PLEKHN1 was expressed in several cancer cell lines of differing origin. Its expression was regulated by hypoxia, and it existed in the mitochondrial fraction. Genome editing of hPLEKHN1 in human colon cancer HT-29 cells revealed enhanced survival of knockout cells compared with that of parental cells in vitro and in vivo. Thapsigargin or hydrogen peroxide treatment activated multiple death signals including JNK, Bcl-2 family members, and caspases. PLEKHN1 was bound to Bid, a pro-apoptotic protein, and not to Bax, and PLEKHN1 could remove Bid from transient Bid–Bax complexes. Fluorescent time-lapse imaging revealed that PLEKHN1 aggregated with Bid during thapsigargin- or hydrogen peroxide-induced apoptosis prior to Bax aggregation. Inhibition of PLEKHN1 led to attenuation of Bax-Bak hetero-oligomerization and Bid translocation. The immunohistochemistry of cancer patient specimens showed that PLEKHN1 expression was absent from cancer region at the transition area of normal/cancer tissues. Collectively, the silencing of PLEKHN1 may be the key that cancer cells acquire the drug resistance.
Highlights
Pleckstrin-homology N1 (PLEKHN1) was reported as cardiolipin phosphatidic acid binding protein[1]
We performed the genome editing in colon cancer cell line, HT-29, and the clone 8 had a large insertion in the genomic region (Fig. 1b), and the full-length hPLEKHN1 protein was abolished (Fig. 1c)
Here we reported that PLEKHN1 acts as a novel member of pro-apoptotic proteins
Summary
Pleckstrin-homology N1 (PLEKHN1) was reported as cardiolipin phosphatidic acid binding protein[1]. It associates with microtubules and accumulates in RNA granules, which contain cytochrome-c mRNA1; its role in cancer has not yet been elucidated. We searched NC-specific genes from the expression database in frog (XDB3.2, NIBB, JAPAN), and found that the frog homolog of PLEKHN1 was required for NCdevelopment (unpublished data). This directed us to investigate the human PLEKHN1 homolog in cancer field. Prolonged hypoxia causes oxidative stress and cellular cytotoxicity[5]
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