Lysosomes and endoplasmic reticulum: Targets for improved, selective anticancer therapy

Drug Resistance Updates 8 (2005) 199–204

Lysosomes and endoplasmic reticulum: Targets for improved, selective anticancer therapy Stig Linder ∗ , Maria C. Shoshan R8:03, Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute and Hospital, S-171 76 Stockholm, Sweden Received 30 May 2005; received in revised form 8 June 2005; accepted 8 June 2005

Abstract Most currently used anticancer agents are active against proliferating cells. Apoptosis signaling mechanisms induced by many such agents are impaired in tumor cells, leading to therapy resistance. Lysosomes and the endoplasmic reticulum (ER) hold promise as drug targets and mediators of apoptosis signaling which may be less affected by intrinsic or chemotherapy-induced resistance mechanisms. Tumor cell lysosomes contain increased levels of cathepsins, and the release of these enzymes into the cytosol may result in apoptosis or necrosis, as has been reported for TNF-␣. It is also reported that tumor transformation leads to increased sensitivity to cathepsin B-dependent apoptosis. Tumor cells often show evidence of constitutive ER stress, possibly due to hypoxia and glucose depletion. Various anticancer drugs, including cisplatin and proteasome inhibitors, have been shown to induce ER stress. Manipulating the ER stress response of tumor cells is an interesting therapeutic strategy. We conclude that organelle damage responses can be used to trigger tumor cell death, and that the response to such damage may be triggered in cells that are resistant to conventional DNA-damaging agents. © 2005 Elsevier Ltd. All rights reserved. Keywords: Cell organelles; Lysosomes; Endoplasmic reticulum; Apoptosis; Proteasome; Bortezomib

1. Introduction During tumor progression, tumor cells are continuously selected for rapid proliferation and survival in the tumor microenvironment. The tumor cell becomes resistant to hypoxia-induced apoptosis (Graeber et al., 1994) and develops optimized survival under conditions of nutrition depletion (Edinger and Thompson, 2002; Lum et al., 2005). An increased overall survival and resistance to unfavorable growth conditions develops as the consequence of several mechanisms, such as mutations in p53, upregulation of PI3K-AKT signaling and growth factor receptor associated pathways. It is unfortunate that the very same pathways that are mutated in cancer cells are associated with resistance to many forms of cancer therapy (Vasilevskaya and O’Dwyer, 2003; Gasco and Crook, 2003). Anticancer therapy should

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for obvious reasons be directed against targets that represent weaknesses in the armour of tumor cells, and not their strong points. Some apoptosis mechanisms are unlikely to be mutated during tumor progression and are therefore interesting potential therapeutic targets. One such potential mechanism is the lysosomal apoptotic pathway. The high protein turnover in tumor cells is another example of a possible weak point to be exploited. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. The aim of this review is to discuss the therapeutic potential of organelleinduced apoptosis.

2. The lysosome as drug target The lysosome was described by De Duve and collaborators 50 years ago (de Duve, 1983) as an organelle rich in acidic hydrolases. The lysosome was for a long time considered to exclusively be a “cell dump station”, involved in degradation of phagocytized material and in general protein

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turnover (de Duve, 1983). Lysosomes are now known to be dynamic organelles that interact with other intracellular compartments, notably the nucleus, mitochondria and the plasma membrane. Three intracellular acid compartments can be distinguished: early endosomes (intraluminal pH of 6.0–6.5), late endosomes (intraluminal pH of ∼5) and lysosomes (with a pH of 4.5 or lower). Transport from late endosomes to lysosomes is believed to occur by carrier vesicles or perhaps by transient fusion events. Newly synthesized lysosomal acid hydrolases are delivered to early and late endosomes. These compartments probably have different functions and can be distinguished by markers such as LAMP1, LAMP2, MPR300 and EEA1. Proteases of the cathepsin family are the best-characterized lysosomal hydrolases. Most cathepsins are cysteineproteases (cathepsin B, C, H, F, K, L, O, S, V, W and X/Z). Two of the cathepsins are aspartyl proteases (cathepsin D and E) and one is a serine protease (cathepsin G). The enzymes are active and stable at low pH, whereas at neutral pH they may be highly active but show variable stability (Turk et al., 2001). Members of the cathepsin family are involved in various physiological and pathological processes such as bone remodeling, hair follicle morphogenesis, antigen presentation and wound healing (reviewed in Turk et al., 2001). Some cathepsins have also been implicated in tumor invasion and metastasis, and are associated with poor prognosis of breast cancer and other cancers (Spyratos et al., 1989). The total concentration of cathepsins in the lysosomes has been claimed to exceed 1 mM (Turk et al., 2001). Rupture of lysosomes, leading to the release of their cathepsin content, has long been recognized as potentially harmful for the cell. The cytosol contains endogenous cysteine cathepsin inhibitors, cystatins (Turk and Bode, 1991), whereas no endogenous cathepsin D/E inhibitors have been described. The degree of lysosomal permeabilization will determine the amounts of cathepsins released into the cytosol: a complete breakdown of all lysosomes will result in necrosis, whereas partial breakdown (sufficient to overcome protection by the cystatins) may trigger apoptosis (Bursch, 2001; Guicciardi et al., 2004). Recent research has shown that lysosomes have important functions in some forms of apoptotic cell death (reviewed in Fehrenbacher and Jaattela, 2005; Guicciardi et al., 2004; Leist and Jaattela, 2001). Injection of cathepsin D to the cytosol of fibroblasts will per se induce caspasedependent apoptosis (Roberg et al., 2002). Some cathepsins can induce pro-apoptotic cleavage of the BH3-only (Bcl-2 homology-3) protein Bid (Cirman et al., 2004), leading to activation of the ability of Bid to act on other pro-apoptotic members of the Bcl-2 family (Korsmeyer et al., 2000). Tumor cells may be preferentially sensitive to agents that trigger the lysosomal apoptosis pathway. In a recent study, Fehrenbacher et al. (2004) demonstrated that immortalization/transformation of mouse embryo fibroblasts increases the sensitivity to TNF-␣ (an agent that induces lysosomal permeabilization, see below). Interestingly, this did not apply

Fig. 1. Tumor cell organelles as drug targets. Lysosomes may rupture preferentially in tumor cells and release high amounts of cathepsins into the cytosol. Tumor cells show constitutive ER stress, and manipulation of ER chaperones or proteasome activity may induce apoptosis.

to cathepsin B−/− fibroblasts, which remained insensitive to TNF-␣ after immortalization. The lysosomal permeabilization pathway therefore offers a therapeutic window between cancer cells and normal tissue (Fig. 1). Different possible mechanisms underlying this preferential sensitivity are listed in Table 1. Many human tumors have increased levels of several cysteine cathepsins (Yan et al., 1998) as well as of cathepsin D (Rochefort et al., 2000), and lysosomal rupture will therefore lead to the release of larger amounts of cathepsins in tumor cells. Interestingly, it has also been reported that cathepsin B-defective cells show increased sensitivity to TNF-␣ induced lysosomal permeabilization (Werneburg

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Table 1 Effect of various conditions typical of tumors/tumor cells on organelle status Tumor (cell) feature

Endoplasmic reticulum

Lysosome

Mitochondrion

Rapid cell division

High protein synthesis

High rate of DNA synthesis, sensitivity to DNA damage Increased levels of misfolded proteins

High cathepsin expression Hypoxia High ROS Acidosis Altered glucose metabolism

Nucleus

Misfolding due to impaired S–S bridge formation Increased peroxidation, carbonylation ER stress Glucose starvation: errors in glycosylation

Increased protein turnover, decreased autophagy Severe consequences of lysosomal rupture

Membrane instability

Damage to mitochondrial DNA

DNA damage

Larger lysosomes Increased levels of glucose metabolites: increased cathepsin expression

et al., 2002), suggesting an active role of the cathepsin B in induction of lysosomal rupture. The probability of lysosomal leakage may be increased due to increased protein turnover in rapidly growing cells (Fehrenbacher and Jaattela, 2005). Tumor cells have been reported to have larger lysosomes (Glunde et al., 2003), and large lysosomes may be more susceptible to breakage (Ono et al., 2003). Finally, in tumor cells, a high turnover of iron-containing proteins leads to lysosomal accumulation of free iron. In combination with increased oxidative stress this may lead to formation of hydroxyl ions via Fenton chemistry, in turn leading to destabilization of lysosomal membranes (Zdolsek et al., 1993). Carcinoma cells, which produce high levels of reactive oxygen species (ROS) (Pelicano et al., 2004; Storz, 2005), may be close to exhausting their antioxidant capacity and could therefore be especially vulnerable to drug-induced increases in oxidative stress. The lysosomal death pathway is attracting considerable interest as a drug target. Examples of stimuli that induce lysosomal apoptotic signaling include TNF-␣ (Foghsgaard et al., 2001; Guicciardi et al., 2000), FAS (Brunk and Svensson, 1999), p53 activation (Yuan et al., 2002), oxidative stress and growth factor deprivation (Brunk and Svensson, 1999) and staurosporine (Emert-Sedlak et al., 2005; Johansson et al., 2003). TNF-␣ and TRAIL are currently being evaluated as cancer therapeutics (Mocellin et al., 2005; Walczak et al., 1999). A recent study suggested that a large number of potential cancer therapeutics induce the lysosomal apoptosis pathway (Erdal et al., 2005). A drug library was screened for compounds that induce apoptosis in p53 defective cells, and seven out of 15 “p53-independent” drugs induced lysosomal permeabilization. Recent evidence has suggested that cathepsin D is involved in apoptosis induced by a number of conventional anti-cancer agents, including etoposide, cisplatin and 5-fluorouracil (Emert-Sedlak et al., 2005). The mechanisms leading to release of cathepsin from the lysosomes after treatment with these agents are unclear as is the relative importance

of the lysosomal pathway for the cytotoxicity of these compounds. Photodynamic therapy (PDT) is based on compounds, which upon illumination with specific wavelengths generate ROS, notably singlet oxygen, leading to apoptosis and/or necrosis. It is known that many PDT drugs have specific subcellular localizations. The hypocrellins are among the most studied and used photosensitizers and have been shown to localize to mitochondria and lysosomes where they induce permeabilization involved in apoptosis (Ali et al., 2002). In summary, tumorigenesis appears to increase the cellular role of lysosomes/cathepsins, and to affect control of lysosomal stability in multiple ways. Future research on the nature of the signals leading to drug-induced permeabilization of cancer cell lysosomes, and on cancer cell inhibition of lysosomal permeabilization will support development of anticancer drugs that target tumor cell lysosomes.

3. The ER as drug target Proteins destined for secretion or for the plasma membrane are translocated into the lumen of the endoplasmic reticulum (ER) where they are modified and acquire their correct folding conformation (Ellgaard et al., 1999). Accumulation of misfolded proteins in the ER triggers signals often referred to as “ER stress” or “unfolded protein response (UPR)”. The ER stress response includes: (1) transcriptional induction of ER chaperones and folding enzymes, such as GRP78, GRP94, and protein disulfide isomerase (Lee, 2001); (2) translational attenuation to prevent further load of proteins into the ER; and (3) ER-associated degradation (ERAD) to clear misfolded proteins out of the ER. Major mediators of transcriptional induction during ER stress are the transcription factors ATF6 and XBP-1 which activate transcription of ER chaperone genes (Yoshida et al., 1998). Excessive ER stress leads to apoptosis. Although it involves factors involved in “standard”, non-ER stress

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responses, the mechanisms appear to differ. Thus, activated IRE1 recruits TRAF2 to the ER membrane (Urano et al., 2000). TRAF2 may in turn activate the apoptosis-signaling kinase 1 (ASK1), leading to activation of JNK known to be required for apoptosis (Nishitoh et al., 2002). Release of Ca2+ from the ER results in activation of Ca2+ activated calpains which have been shown to cleave intracellular substrates related to apoptotic signaling, including Bid (Mandic et al., 2002), Bax (Wood et al., 1998), caspase-7 (Ruiz-Vela et al., 1999) and mouse caspase-12 (Nakagawa and Yuan, 2000). In human cells, caspase-4 localized to the ER membrane is cleaved and activated when cells are treated with ER stressinducing reagents (Hitomi et al., 2004). CHOP/GADD153, a C/EBP family transcription factor and DR5 also appear to play key roles in ER-mediated cell death, especially in disruption of Ca2+ homeostasis (He et al., 2003; Yamaguchi and Wang, 2004). DR5 upregulation may be expected to increase the tumor-specific effect of TRAIL; this could explain the sensitizing effect of thapsigargin to TRAIL-induced cell death (Huang et al., 2004) (see below). A number of different agents have been reported to directly induce ER stress: glycosylation inhibitors (e.g. tunicamycin and 2-deoxyglucose), agents that deplete ER Ca2+ (e.g. the sarcoendoplasmic-reticulum Ca2+ -ATPase inhibitor thapsigargin and various ionophores) and agents that induce reductive stress (dithiotreitol and ␤-mercaptoethanol) (Lee, 2001). Some evidence suggests that ER stress-inducing agents are useful as cancer agents, although the evidence is meager. Thapsigargin sensitizes tumor cells to TRAIL-induced cell death (Huang et al., 2004), and tunicamycin increased the sensitivity of head-and-neck tumor cell lines to cisplatin in vitro and in vivo (Noda et al., 1999). A prostate specific antigen (PSA)-activated thapsigargin prodrug has been characterized that is selectively toxic to PSA-producing prostate cancer cells in vitro and in vivo (Denmeade et al., 2003). Moreover, several photosensitizers, such as porphyrin and Foscan, have been shown to localize to the ER and the Golgi (reviewed by Piette et al., 2003). However, their effect is likely one of membrane damage rather than standard ER stress. ER-related responses may be part of the overall effects induced by other chemotherapeutic agents. We have found that the anticancer agent cisplatin induces some types of ER stress, as evidenced by release of Ca2+ and increased expression of GRP78 (Mandic et al., 2003) and that a derivative of the plant alkaloid ellipticine induces both transcription from ER stress elements and induces XBP1 splicing (H¨agg et al., 2004). Doxorubicin induces ER stress in vivo, as shown by ER-specific caspase-12 activation in rats (Jang et al., 2004). However, tumor cells show signs of constitutive ER stress, as indicated by overexpression of ER chaperones, calreticulin and calnexin (Chen et al., 2002; Little et al., 1994). Contributing factors may be glucose starvation in regions of tumors that are distant from vessels, and low pH (Lee, 2001). Furthermore, hypoxia induces GRP78 expression via a PKC/ERK pathway (Song et al., 2001). Overexpression of ER chaperones has been associated with

resistance to chemotherapeutic agents (Lin et al., 1998; Mandic et al., 2003; Reddy et al., 2003). Direct overexpression of GRP78 by transfection results in increased resistance to topoisomerase I and II inhibitors, possibly due to binding of caspase-7 to GRP78 in the ER (Reddy et al., 2003). If constitutive low-level ER stress in tumor cells confers a measure of protection, in particular via the unfolded protein response (UPR), it is of interest to reduce this particular response in tumor cells (Fig. 1). Indeed, degradation of misfolded proteins will per se prevent ER-mediated cell death (Haynes et al., 2004). Inhibition of the physiological UPR may thus be a highly efficient and tumor-specific strategy, as exemplified by versipelostatin (VST), a compound that inhibits transcription from the GRP78 promoter (Park et al., 2004). VST also inhibited the production of XBP1 and ATF4 during glucose deprivation. VST caused selective and massive killing of the glucose-deprived cells and significantly inhibited tumor growth alone and in combination with cisplatin. Similar findings have been reported using proteasome inhibitors. Misfolded ER proteins are translocated from the ER lumen and degraded by the proteasome (Fig. 1). Bortezomib (also known as PS-341 or Velcade), the first proteasome inhibitor to enter clinical practice, induces apoptosis through induction of ER stress (Bush et al., 1997; Fribley et al., 2004; Lee et al., 2003). Interestingly, Bortezomib induces ER stress and also prevents an appropriate unfolded protein response (by inhibition of GRP78 expression and XBP-1 splicing) (Lee et al., 2003). A problem in this field is the definition of “ER stress”. Is a mild induction of the ER chaperone GRP78 a proof of ER stress? GRP78 can be induced by cytokines, similar to delayed-early response genes (Brewer et al., 1997). ER chaperone induction may therefore not be a strict criterion for ER stress and induction of several activities, including XBP1 splicing, should be assessed.

4. Conclusion and future perspective A common misconception is that tumor cells are resistant to apoptosis. This belief is based on the fact that some anti-apoptotic proteins and anti-apoptotic signaling pathways are overexpressed or overactivated in cancer cells, and that mutations in anti-apoptotic proteins are common. The mutant phenotype is selected to confer increased resistance to conditions that the tumor cells have been exposed to during malignant growth (hypoxia, nutrition starvation) that induce apoptosis. However, other apoptosis signaling pathways are probably not selected against and remain intact in tumor cells. One interesting candidate is the lysosomal apoptosis pathway, which is active in cells with p53 mutations. It will be important to unravel the therapeutic use of compounds that induce organelle stress. Chemical libraries may contain many cationic compounds that accumulate in lysosomes or induce lysosomal rupture by other mechanisms, and compounds that

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disturb protein folding in the ER. Thus, candidate drugs to validate and further develop these concepts may be already available.

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