Cholesterol Targeting in Cancer Therapy

MR Freeman1,2,3,4, D Di Vizio1,2,3 and KR Solomon1,2,5

1Urological Diseases Research Center, Children’s Hospital Boston, Boston, MA, USA; 2Department of Urology, Children’s Hospital Boston–Harvard Medical School, Boston, MA, USA; 3Department of Surgery, Children’s Hospital Boston–Harvard Medical School, Boston, MA, USA; 4Department of Biological Chemistry and Molecular Pharmacology, Children’s Hospital Boston–Harvard Medical School, Boston, MA, USA and 5Department of Orthopaedic Surgery, Children’s Hospital Boston–Harvard Medical School, Boston, MA, USA

In this issue of Oncogene, Mollinedo and co-workers present promising evidence that cholesterol-sensitive signaling pathways involving lipid rafts can be therapeutically targeted in multiple myeloma. Because the pathways considered in their study are used by other types of tumor cells, one implication of this report is that cholesterol-targeting approaches may be applicable to other malignancies. Oncogene (2010) 29, 3745–3747; doi:10.1038/onc.2010.132; published online 3 May 2010

Cholesterol is a sterol that serves targeted therapeutically in the case androgens are generally thought to as a metabolic precursor to other of certain malignancies. promote prostate cancer disease bioactive sterols, such as nuclear Published evidence suggests that progression, the relative clarity of receptor ligands, and also has a a cholesterol-focused approach the epidemiological data in pros- major role in plasma membrane might work in some clinical scenar- tate cancer in comparison to other structure. Cholesterol and long- ios. Cholesterol-lowering drugs that organ sites may arise from the role chain sphingolipids are believed inhibit the enzyme HMG-CoA of cholesterol as the synthetic pre- to accumulate in ‘liquid-ordered’ reductase, which catalyzes the rate- cursor of androgens. patches termed lipid rafts, which limiting step in cholesterol synthesis The paper by Mollinedo et al. in are distinct in dynamic behavior (these drugs are generically termed this issue, along with previous from cholesterol-poor regions of ‘statins’), have been reported to studies from this group and from the membrane. Biophysical, bio- inhibit cancer incidence or progres- other labs, provide persuasive evi- chemical and imaging studies have sion in some studies. Although there dence that membrane cholesterol provided strong evidence that lipid is much controversy, buttressed by itself is a critical mediator of cell rafts exist in biological membranes, claims and counterclaims, in the survival signaling mechanisms that although details of their precise various population-based reports can be effectively targeted with form and stability are still hotly of the effects of statins on cancer, clinically relevant drugs. Because debated. Cholesterol-rich micro- recent evidence published by several this has been shown in multiple domains have been shown to groups examining large prospective myeloma, a malignancy without sequester a variety of membrane- series suggest that prostate cancer the hormone dependence of pros- associated signaling proteins, while progression is likely to be inhibited tate cancer, the in situ production excluding others, and a variety of by long-term cholesterol-lowering of steroid hormones is an unlikely approaches have shown that cho- therapy (Platz et al., 2006; Mondul explanation for the sensitivity to lesterol itself has a role in trans- et al., 2010). These promising re- cholesterol-targeting manipulations. mitting cell growth, survival and sults in humans are in agreement Edelfosine, and the related com- differentiation signals. There has with animal model data, in which pound, perifosine, are prototypic been speculation that cholesterol- cholesterol is raised or lowered and members of a family of synthetic dependent membrane dynamics, prostate tumor growth thereby lipids with tumor-killing properties such as receptor clustering, may be promoted or inhibited, respectively known as alkyl-lysophospholipid (Zhuang et al., 2005; Solomon analogs. Both drugs are presently et al., 2009). Prostate cancer may in human trials and significant be a special case, however, because clinical responses have been Correspondence: Dr MR Freeman, Urological recent observations from several reported. In a series of studies, Diseases Research Center, Enders 1161, groups indicate that tumor cells edelfosine was shown to accumulate Children’s Hospital Boston, 300 Longwood are capable of de novo androgen in cell membrane rafts and cause Avenue, Boston, MA 02115, USA. E-mail: [email protected] synthesis from cholesterol, obviat- co-clustering of components of the Received 14 March 2010; accepted 14 March ing the need to acquire the hor- death-inducing signaling complex, 2010; published online 3 May 2010 mone from the circulation. Because resulting in tumor cell apoptosis. The Rafts of the Medusa MR Freeman et al 3746 Raft disruption by cholesterol de- could be exploited with lipid-target- and exploited. As the tumor meta- pletion, using a variety of distinct ing agents. bolism picture becomes clearer over approaches, inhibits drug uptake by Lipid targeting in cancer therapy the next decade, lipid-targeting stra- tumor cells, preventing apoptosis. is of growing interest because of a tegies should prove relevant to the This inhibition is reverted by reawakened appreciation for the clinical situation, at least for some cholesterol replenishment. in vivo, role of metabolic pathways as es- classes of tumors. Because of shared edelfosine accumulates in mouse sential features of malignant trans- metabolic consequences of cell plasmacytomas, inducing apoptosis. formation and progression (Vander transformation that arise from the However, the drug uptake by the Heiden et al., 2009). Tumor cells many varieties of genetic alterations tumor is reduced if tumor cholester- consume high levels of glucose but in multiple signal transduction ol levels are lowered by statin often simultaneously suppress ATP pathways, one can even imagine therapy, resulting in treatment fail- production, diverting carbon atoms that lipid-targeting approaches ure. These and supporting observa- and reducing equivalents toward may ultimately prove to be more tions strongly suggest that tumor pathways that synthesize macromo- widely efficacious than is currently apoptosis induced by the alkyl- lecules, particularly lipids required the case for drugs directed toward lysophospholipid compounds is for new membrane formation. Up- the major protein signal transduc- cholesterol dependent. regulation of fatty acid synthase, tion targets, such as ErbB family Edelfosine was the first com- the major source of long-chain fatty receptors and other kinases. pound reported to promote apopto- acids (principally palmitate) in There are some caveats that sis by ligand-independent activation tumor cells, is a prominent charac- should be considered when evaluat- of Fas/CD95 death receptors. How- teristic of this metabolic profile ing the fortunes of cholesterol tar- ever, this class of drug may also (Menendez and Lupu, 2007). Lipo- geting. Modeling cholesterol reduc- operate by cholesterol-sensitive me- genesis is also activated by Akt tion in rodents is challenging be- chanisms distinct from death-indu- upregulation, another common cause statin drugs do not lower cing signaling complex formation. event in malignancy. Preclinical circulating cholesterol in mice and Perifosine was shown to potently data have shown that fatty acid rats, as they do in humans. Choles- inhibit activation of the serine-threo- synthase is effectively targetable terol lowering in rodent tumors will nine kinase Akt (Hideshima et al., in vivo and efforts are underway to thus depend on whether the drug 2006), which usually performs a pro- improve the toxicity profile asso- can penetrate sufficiently into the survival function. In other studies, ciated with the available anti-fatty tumor bed, a scenario that does not Akt has been identified as a choles- acid synthase compounds. Inhibit- adequately model the conventional terol-sensitive protein that localizes ing various components of the cholesterol reduction situation in to lipid rafts (Adam et al., 2007), growth factor receptor-PI3- humans, in which the level of consistent with a mechanism of kinase-Akt-mTOR pathway, an extrahepatic statin is low and of action where perifosine alters raft- active area in pharmaceutical R&D, short duration. However, other mediated signaling from Akt. Collec- will produce major alterations in approaches to cholesterol lowering tively, these results suggest that lipid metabolism, only some of in mice have recently been devel- cholesterol/lipid raft targeting may which are known. The landscape oped (Solomon et al., 2009) and cooperatively activate both pro- of tumor cell membranes is drasti- these might be exploited to identify death and inhibit pro-survival path- cally altered from normal as a result cholesterol-sensitive tumor types by ways simultaneously. of shifts in metabolism arising from way of xenografts or transgenic One important issue is that edel- malignant transformation; however, models. Whether the unusually high fosine is taken up specifically by characterization of membrane lipid level of selectivity toward tumor CD138 þ malignant cells obtained composition in tumor cells is still at cells seen with edelfosine will be from patients with multiple myelo- a fairly primitive stage. Given the replicated with other lipid-targeting ma, whereas CD138À normal cells absolute requirement for cholesterol agents is an open question. In from the same patients and normal in the synthesis of mammalian cell addition, high concentrations of peripheral blood lymphocytes did membranes, it follows that rapidly cholesterol are naturally found in not incorporate the drug. Similarly, proliferating tumor cells require the brain, ilium, liver and prostate. edelfosine induced clustering of more cholesterol than normal cells. Consequently, a cholesterol-target- Fas/CD95 and TRAIL receptors in Moreover, the ability of cancer cells ing approach may not be selective lipid rafts in tumor cells, but not in to metastasize may depend on the for tumors at certain anatomical normal cells from the same patients. formation of cholesterol-rich cell sites. It is also not clear whether In vivo, edelfosine concentrated in extensions called invadopodia, edelfosine can cross either the the multiple myeloma tumors but which may not form in the absence blood–brain or blood–testes bar- the drug localized poorly in liver of excess cholesterol (Caldieri and riers, so malignancies at these loca- and kidney. These observations Buccione, 2010). Thus, metastatic tions may not be targetable by suggest that tumor cell memb- cells’ dependence on abnormal le- the alkyl-lysophospholipid class of ranes are substantially altered in vels of cholesterol may prove to be compounds. lipid composition, a consequence their undoing if vulnerabilities in A not unfitting metaphor for of malignant transformation that lipid metabolism can be identified cancer, Medusa was a mythical

Oncogene The Rafts of the Medusa MR Freeman et al 3747 creature, highly feared, with snakes Although most of the castaways of tumors might provide effective in place of hair, which could turn lost their lives in the escape attempt, therapeutic opportunities. someone to stone with a single some were saved by the hastily glance. The Raft of the Medusa constructed raft. It is intriguing that (Le Radeau de la Me´duse) is a the metaphor of the Raft of the famous oil painting by Theódore Medusa providing sanctuary and Conflict of interest Ge´ricault, which depicts a tragic life may someday extend to pa- escape from a wrecked French tients, where the cholesterol- and The authors declare no conflict of naval vessel of the same name. lipid-rich membrane environment interest.

References

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