1. Academic Validation
  2. PLEKHN1 promotes apoptosis by enhancing Bax-Bak hetro-oligomerization through interaction with Bid in human colon cancer

PLEKHN1 promotes apoptosis by enhancing Bax-Bak hetro-oligomerization through interaction with Bid in human colon cancer

  • Cell Death Discov. 2018 Feb 8;4:11. doi: 10.1038/s41420-017-0006-5.
Sei Kuriyama 1 Tadahiro Tsuji 2 Tetsushi Sakuma 3 Takashi Yamamoto 3 Masamistu Tanaka 1
Affiliations

Affiliations

  • 1 1Department of Molecular Medicine and Biochemistry, Faculty and Graduate School of Medicine, Akita University, Akita, Japan.
  • 2 2Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School and Faculty of Medicine, Akita University, Akita, Japan.
  • 3 3Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashihiroshima, Japan.
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.

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