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New light on anti-sphingolipid targeting cancer therapy

The sphingolipid metabolic pathway and in particular the level and subcellular localisation of its catabolic end product ceramide offer potential targets of anti-cancer strategies. In a new publication in Nature Chemical Biology, the joint efforts of NCCR researchers and other external labs identify the lysosomal transmembrane protein, LAPTM4B, as a specific ceramide binding protein and an alternative regulator of ceramide clearance from the late endosomes independently of the known ceramidase-dependent catabolism. This gate-keeper function provides a mechanism by which LAPTM4B modulates sphingolipid mediated cell death mechanisms highly relevant in cancer thus shedding new light on anti-cancer strategies.

In mammalian cells, ceramide not only represents a membrane structural element but an important second messenger involved in several regulatory mechanisms. In particular, this factor acts as a strong tumor suppressor with pro-apoptotic properties. Several commonly used chemotherapeutics induce cell death in a ceramide dependent fashion. The molecule is an intermediate of the sphingolipid metabolic pathway of the most abundant sphingolipid, sphingomyelin (SM) and of other complex sphingolipids. SM catabolism has attracted increasing attention as target for anticancer strategies: manipulation of acid sphingomyelinase – which breaks down the sphingomyelin to the ceramide- and lysosomal membrane permeabilization are being explored as means to kill chemotherapy resistant cancer cells. Ceramides have also been implicated in depression.  The absolute concentration of ceramide but also its subcellular localization seems to be particularly relevant for its tumor-suppressor activity. Sphingolipid catabolism takes place in late endosomes /lysosomes (LE) and the major mechanism for ceramide removal from the LE has been attributed to the acid ceramidase-dependent catabolism, though other mechanisms were suggested as well.

Further insight in the dissection of this ceramide clearance pathway from the LE is published this month in Nature Chemical Biology as a result of the collaboration of several groups including Howard Riezman‘s NCCR UNIGE lab. The authors used novel sphingolipid probes that can be detected and traced only if the ceramide structure is intact and identified a new parallel and acid-ceramidase independent pathway. They identified one of the lysosomal membrane spanning LAPTM family of proteins, LAPTM4B, as the key regulatory target to remove SM degradation products from LE. LAPTM4B is known as a nucleoside transporter and a modulator of drug compartmentalization relevant to cancer progression by several mechanisms and either high or low expression might confer a poor anti-cancer drug response. In the results presented, LAPTM4B binds specifically ceramide and regulates ceramide clearance from the LE. Most importantly, its expression level and ceramide compartmentalization function between intra- and extra endosomal pools modulate apoptosis sensitivity. LAPTM4B depleted cells have an elevated intra endosomal ceramide content, show signs of LE and lysosomal membrane destabilisation and resist apoptotic ceramide-driven caspase-3 activation and apoptosis induced by chemotherapeutic agents or gene silencing.  Conversely, LAPTM4B overexpression reduces LE ceramide and stabilizes lysosomes but sensitizes to drug-induced caspase-3 activation. The precise mechanism and regions of LAPTM4B controlling the ceramide export mechanism from LE will be addressed in future studies.

By regulating the subcellular compartmentalization of ceramide, LAPTM4B seems to control key sphingolipid mediated cell death mechanisms and emerges as a new candidate for sphingolipid targeting cancer therapies.

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