Abstract
SMAC/Diablo, a pro‐apoptotic protein, yet it is overexpressed in several cancer types. We have described a noncanonical function for SMAC/Diablo as a regulator of lipid synthesis during cancer cell proliferation and development. Here, we explore the molecular mechanism through which SMAC/Diablo regulates phospholipid synthesis. We showed that SMAC/Diablo directly interacts with mitochondrial phosphatidylserine decarboxylase (PSD) and inhibits its catalytic activity during synthesis of phosphatidylethanolamine (PE) from phosphatidylserine (PS). Unlike other phospholipids (PLs), PE is synthesized not only in the endoplasmic reticulum but also in mitochondria. As a result, PSD activity and mitochondrial PE levels were increased in the mitochondria of SMAC/Diablo‐deficient cancer cells, with the total amount of cellular PLs and phosphatidylcholine (PC) being lower as compared to SMAC‐expressing cancer cells. Moreover, in the absence of SMAC/Diablo, PSD inhibited cancer cell proliferation by catalysing the overproduction of mitochondrial PE and depleting the cellular levels of PC, PE and PS. Additionally, we demonstrated that both SMAC/Diablo and PSD colocalization in the nucleus resulted in increased levels of nuclear PE, that acts as a signalling molecule in regulating several nuclear activities. By using a peptide array composed of 768‐peptides derived from 11 SMAC‐interacting proteins, we identified six nuclear proteins ARNT, BIRC2, MAML2, NR4A1, BIRC5 and HTRA2 Five of them also interacted with PSD through motifs that are not involved in SMAC binding. Synthetic peptides carrying the PSD‐interacting motifs of these proteins could bind purified PSD and inhibit the PSD catalytic activity. When targeted specifically to the mitochondria or the nucleus, these synthetic peptides inhibited cancer cell proliferation. To our knowledge, these are the first reported inhibitors of PSD acting also as inhibitors of cancer cell proliferation. Altogether, we demonstrated that phospholipid metabolism and PE synthesis regulated by the SMAC‐PSD interaction are essential for cancer cell proliferation and may be potentially targeted for treating cancer.
Highlights
Alteration of tumour metabolism, including lipid metabolism is involved in carcinogenesis with cancer cells demonstrates a high dependence on lipids [1]
Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies
We recently demonstrated that silencing SMAC/Diablo expression using specific siRNA in subcutaneous xenografts of lung cancer A549 cells in mice reduced tumour growth [21]
Summary
Alteration of tumour metabolism, including lipid metabolism is involved in carcinogenesis with cancer cells demonstrates a high dependence on lipids [1]. Phospholipids (PLs) are essential building-block components of cellular membranes, but act as regulators for various cellular functions, such as cell adhesion and migration, neurotransmission, signal transduction, vesicular trafficking, apoptosis, metabolism and post-translational modifications [2]. Distribution and metabolism of PLs in cells, tissues and body fluids (blood, urine) are associated with cancer and other diseases [3]. Phosphatidylethanolamine (PE), the focus of this study, is the second most abundant phospholipid on mammalian cellular membranes. Besides functioning as a membrane structural element, PE participates in many important pathophysiological cellular processes [8]. PE’s importance for appropriate cancer cell function is demonstrated in this study
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