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Cell Biology International (2010) 34, 2125 (Printed in Great Britain)
Cyclo-oxygenase 2 up-regulates the effect of multidrug resistance
Bing Liu*1, Liyan Qu†1 and Huimin Tao*2
*Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, #88 Jie Fang Road, Hangzhou, 310009, Zhejiang, People's Republic of China, and †Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, #388 Yuhang Tang Road, Hangzhou, 310058, Zhejiang, People's Republic of China
COX-2 (cyclo-oxygenase 2), an inducible form of the enzyme that catalyses the first step in the synthesis of prostanoids, is associated with inflammatory diseases and carcinogenesis, which is suspected to promote angiogenesis and tissue invasion of tumours and resistance to apoptosis. COX-2 is also involved in drug resistance and poor prognosis of many neoplastic diseases or cancers. The activation of the COX-2/PGE2 (prostaglandin E2)/prostaglandin E receptor signal pathway can up-regulate the expression of all three ABC (ATP-binding-cassette) transporters, MDR1/P-gp (multidrug resistance/P-glycoprotein), MRP1 (multidrug-resistance protein 1) and BCRP (breast-cancer-resistance protein), which encode efflux pumps, playing important roles in the development of multidrug resistance. In addition, COX inhibitors inhibit the expression of MDR1/P-gp, MRP1 and BCRP and enhance the cytotoxicity of anticancer drugs. Therefore we can use the COX inhibitors to potentialize the effects of chemotherapeutic agents and reverse multidrug resistance to facilitate the patient who may benefit from addition of COX inhibitors to standard cytotoxic therapy.
Key words: breast-cancer-resistance protein (BCRP), cyclo-oxygenase 2 (COX-2), cyclo-oxygenase inhibitor, multidrug resistance/P-glycoprotein (MDR1/P-gp), multidrug-resistance protein 1 (MRP1)
Abbreviations: AA, arachidonic acid, ABC, ATP-binding-cassette, AC, adenylyl cyclase, BCRP, breast-cancer-resistance protein, COX, cyclo-oxygenase, cPGES, cytosolic PGE2 synthase, EGR-1, early growth response factor 1, EP, prostaglandin E receptor, ERK, extracellular-signal-regulated kinase, MDR, multidrug resistance, mPGES, microsomal PGE2 synthase, MRP, multidrug-resistance protein, NSAID, non-steroidal anti-inflammatory drug, PG, prostaglandin, P-gp, P-glycoprotein, PI3K, phosphoinositide 3-kinase, PKA, protein kinase A, PKB, protein kinase B, TXA2, thromboxane A2
1These authors contributed equally to the present study.
2To whom correspondence should be addressed (email email@example.com).
Human malignancies generally arise as the culmination of a multistep process that involves a variety of somatic gene alterations. Nowadays, researchers have focused on the gene-based therapies, which include either suppression of overexpressed oncogenes or induction of low-expressed tumour suppressor genes. Therefore we are trying to find drugs which can affect gene expression and achieve the therapies for human malignancies. It has been shown that in most solid tumours, such as colorectal, liver, pancreatic, breast and lung cancers, COX-2 (cyclo-oxygenase 2) is overexpressed (Eberhart et al., 1994; Hida et al., 1998; Hwang et al., 1998; Koga et al., 1999; Tucker et al., 1999). Both selective NSAIDs (non-steroidal anti-inflammatory drugs) and non-selective COX-2 inhibitors can inhibit proliferation, invasiveness of tumours and angiogenesis and overcome apoptosis and drug resistance (Harris et al., 2008).
Intrinsic or acquired resistance to chemotherapeutic drugs is the major obstacle to successful chemotherapy. The most frequent form of resistance observed in cancer patients is MDR (multidrug resistance). Mechanisms underlying the development of MDR have been extensively studied and are considered multifactorial. The overexpression of the ABC (ATP-binding cassette) superfamily of transporters, which act as pumps to extrude anticancer drugs, plays a pivotal role. Among the ABC transporters, MRP1 (multidrug-resistance protein-1) and P-gp (P-glycoprotein) are frequently overexpressed in drug-resistant cancer cells; the latter is encoded by the human MDR1 gene (Thiebaut et al., 1987).
Immunohistochemical analyses of human breast tumour specimens revealed a strong correlation between expression of COX-2 and MDR1/P-gp (Ratnasinghe et al., 2001). Moreover, the expression of the COX-2 enzyme may up-regulate expression of MDR1/P-gp (Surowiak et al., 2005). Therefore COX-2 inhibitors should be used to suppress the function of MDR1, which may enhance the accumulation of chemotherapy agents and decrease the resistance of tumours to chemotherapeutic drugs (Sorokin, 2004).
COX is an enzyme, also known as PG (prostaglandin) rate-limiting synthase, that catalyses the conversion of AA (arachidonic acid) into PGs. Finally, a series of biologically active prostaglandins (PGD2, PGE2, PGF2α and PGI2) and TXA2 (thromboxane A2) are formed. There are three isoforms of the enzyme that have been identified: COX-1, COX-2 and COX-3. COX-1 is considered a ‘housekeeping enzyme', constitutively expressed in human cells (Vane and Botting, 1995). COX-3, an alternative splice variant of COX-1, is most abundant in the canine cerebral cortex (Chandrasekharan et al., 2002). COX-2 is an inducible enzyme and is associated with inflammatory diseases and carcinogenesis, which is suspected to promote angiogenesis and tissue invasion of tumours (Tsujii et al., 1997, 1998) and resistance to apoptosis (Tsujii and DuBois, 1995; Nzeako et al., 2002). COX-2 is also involved in drug resistance and poor prognosis of tumour (Fantappiè et al., 2007).
3. COX-2/PGE2/EP (prostaglandin E receptor) signalling pathway
AA is transformed into an unstable intermediate PGG2, which is promptly converted into PGH2 by COX, and finally into five primary PGs (PGD2, PGE2, PGF2α, TXA2 and PGI2) by cell-specific synthases. The actions of these prostanoid ligands are mediated by their engagement of specific cell-surface G-protein-coupled receptors designated EP1–4 for PGE2 and PGF2α receptor, PGD2 receptor, PGI2 receptor and TXA2 receptor for PGF2, PGD2, PGI2 and TXA2 respectively (Greenhough et al., 2009).
Both COX-1 and COX-2 are capable of converting AA into prostaglandins, but they exhibit a preference for synthesizing prostaglandins (Yang and Chen, 2008). It has been demonstrated that PGE2 and PGI2 are mainly derived from the COX-2 pathway (Brock et al., 1999). PGE2 is generated from PGH2 by cPGES (cytosolic PGE2 synthase) and membrane-bound mPGES-1 and -2 (microsomal PGE2 synthase-1 and -2). cPGES is mainly involved in COX-1, mPGES-1, however, is preferentially coupled with COX-2, and mPGES-2 is linked with both COX-1 and COX-2 (Claveau et al., 2003; Murakami et al., 2003). Once PGE2 is synthesized, it diffuses immediately and activates its specific membrane receptors (EP1–4). EP1 receptors couple with the Gq/PLC (phospholipase C)/IP3 (inositol trisphosphate) pathway, and its activation results in the release of intracellular Ca2+. EP2 and EP4 receptors couple with the Gs/AC (adenylyl cyclase)/cAMP/PKA (protein kinase A) pathway. EP3 couples with a pertussis toxin-sensitive Gi protein to inhibit AC, resulting in a decrease in cAMP (Yang and Chen, 2008).
It is widely accepted that alterations to COX-2 expression and the abundance of its enzymatic product PGE2 play key roles in influencing the development of cancers, because its level is markedly elevated in tissues of cancers (Eberhart et al., 1994; Hida et al., 1998; Hwang et al., 1998; Koga et al., 1999; Tucker et al., 1999; Greenhough et al., 2009). Deregulation of the COX-2/PGE2 pathway appears to affect colorectal tumorigenesis via a number of distinct mechanisms: promoting tumour maintenance and progression, encouraging metastatic spread, and perhaps even participating in tumour initiation (Hawcroft et al., 2007; Tanaka et al., 2008). Chell et al. (2006) reported that in vivo EP4 receptor protein expression was increased in colorectal cancers (100%) as well as adenomas (36%) when compared with normal colonic epithelium, as measured using immunohistochemistry. PGE2 signalling through the EP4 receptor has previously been associated with colorectal tumorigenesis. Fujino et al. (2002) reported that EP2 receptor-mediated activation of Tcf (T-cell factor) transcriptional activity was primarily through a cAMP/PKA-dependent mechanism; whereas, EP4 receptor-mediated activation occured primarily through a PI3K (phosphoinositide 3-kinase)-dependent pathway. Previously, it has been found that PGE2 stimulation of EP4 receptors activated an additional PI3K-dependent pathway leading to the phosphorylation of the ERKs (extracellular-signal-regulated kinases), followed by induction of the functional expression of EGR-1 (early growth response factor 1) (Fujino et al., 2002). ERK phosphorylation and induction of EGR-1 expression was unique for EP4 receptors and was not observed in cells that expressed EP2 receptors (Fujino et al., 2002, 2003; Fujino and Regan, 2003). Cyclin D1, a key regulator of cell-cycle progression, is under the control of EGR-1 through a PI3K- and ERK-dependent pathway (Guillemot et al., 2001). EP4-dependent activation of PI3K/Akt signalling has been reported to stimulate the proliferation and motility of colorectal cancer cells (Sheng et al., 2001). Therefore this suggests a possible role for EP4 receptors in cancers.
The role that EP2 receptors play in cancers is still controversial. Sonoshita et al. (2001) showed that homozygous deletion of the gene encoding EP2 caused decreases in the number and size of intestinal polyps in ApcΔ716 mice (a mouse model for human familial adenomatous polyposis). Homozygous gene knockout for other PGE2 receptors, EP1 or EP3, did not affect intestinal polyp formation in ApcΔ716 mice. Fujino et al. (2002) suggested that the increased expression of COX-2 via EP2 receptors and an increased expression of PGE2 synthase via EP4 receptors could explain the increased biosynthesis of PGE2 known to occur in colon cancer.
Above all, the COX-2/PGE2/EP4 signalling pathway plays an important part in the development of cancers; therefore the EP4 receptor may represent an important target for cancer prevention and treatment.
4. Multidrug resistance
Chemotherapy efficacy is influenced by intrinsic or acquired MDR, and MDR is a significant barrier to effective chemotherapy of cancer. It has been established that membrane proteins, notably P-gp, MRP and BCRP (breast-cancer-resistance protein) of the ABC transporter family encoding efflux pumps, play important roles in the development of MDR (Kuo, 2009).
MDR belongs to the B group of the ABC transporter superfamily (Higgins, 2007). Two P-gps encoded by MDR genes have been found in humans, MDR1 (ABCB1) and MDR2 (ABCB2) (Limtrakul et al., 2007; Daood et al., 2008). The human MDR1/P-gp1 gene is expressed in many normal tissues, including the liver, kidney, small intestine, colon, adrenal gland and the blood–brain barrier. However, MDR2/P-gp2 is expressed mainly in the liver and kidney. Only P-gp1 functions as an antitumour drug transporter, which transports a wide range of compounds, such as doxorubicin, vincristine and taxanes, etoposide, teniposide and actinomycin D etc., preferentially hydrophopic cationic compounds, from the inside of the cell back to the extracellular space, leading to a decrease in drug concentration within the cell and a reduced cancer-chemotherapy efficacy (Kuo, 2009).
Nine members of the MRP family are found in the human genome, designated MRP1–MRP9 (Haimeur et al., 2004). MRP1 was first identified in the doxorubicin-resistant small-cell lung cancer cell line H69AR that did not overexpress P-gp (Cole et al., 1992), which is ubiquitously expressed in the human body (Cascorbi, 2006). MRP2 facilitates transport of anticancer agents, including cisplatin, vinblastin and camptothecin derivatives (Borst et al., 1999). Both MRP1- and MRP2-mediated efflux require cofactors, glutathione GSH, glucuronic acid or sulfate (Kuo, 2009).
BCRP is a 655-amino-acid polypeptide, formally designated as ABCG2 (Lage and Dietel, 2000). Overexpression of BCRP is associated with high levels of resistance to a variety of anticancer agents, including anthracyclines, mitoxantrone and the camptothecins, by enhancing drug efflux (Doyle and Ross, 2003). BCRP expression has been detected in a large number of haematological malignancies and solid tumours, indicating that this transporter may play an important role in clinical drug resistance of cancers (Mao and Unadkat, 2005).
5. COX-2 up-regulates the expression of MDR1/P-gp, MRP1 and BCRP
Previously, a causal link between COX-2 and MDR-1 gene expression, implicated in cancer chemoresistance, has been demonstrated. Patel et al. (2002) showed that the overexpression of COX-2 led to increased P-gp expression and activity in rat mesangial cells, and this effect was dependent on COX-2 activity. In addition, the specific COX-2 inhibitor NS398 was able to block the COX-2-mediated increase in MDR1 expression and activity, suggesting that PGE2 may be implicated in this response (Patel et al., 2002). In patients with gastric cancer, it has been revealed that the expression of COX-2 and the downstream enzyme involved in PGE2 biosynthesis, mPGES1, was correlated with P-gp and Bcl-xL (Nardone et al., 2004). In colon cancer, COX-2 overexpression induced increased MRP-1 expression, resulting in chemoresistance to cisplatin (Saikawa et al., 2004). A strong positive correlation between the expression of COX-2 and MDR1/P-gp was also observed in hepatocellular carcinoma, breast cancer and ovarian cancer (Ziemann et al., 2002; Surowiak et al., 2005, 2006). COX-2 may be a factor that can regulate the expression of all three ABC transporters: MDR1/P-gp, MRP1 and BCRP (Surowiak et al., 2008).
NSAIDs and COX-2 selective inhibitors have been demonstrated to overcome MDR in many cancers. It has been suggested that COX inhibitors may sensitize cancer cells to chemotherapeutic drugs via inhibiting P-gp, MRP1 and BCRP, thus enhancing the effect of anticancer drugs (Arico et al., 2002; Zatelli et al., 2007; Arunasree et al., 2008; Liu et al., 2008). In imatinib-resistant K562 cells, celecoxib can inhibit COX-2 and down-regulate MDR-1 expression through the Akt/PKB (protein kinase B) signalling pathway (Arunasree at al., 2008). Akt/PKB belongs to the downstream molecules of PI3K, which play an important role in the PGE2/EP4 pathway, as shown above. COX-2 inhibitors are known to inhibit the PI3K/Akt pathway (Arico et al., 2002). We have confirmed that celecoxib induced apoptosis in a human osteosarcoma cell line MG-63 via down-regulation of PI3K/Akt, as well as potentiating the effect of cisplatin (Liu et al., 2008). In breast cancer, COX-2 inhibitors can also inhibit P-gp expression and function (Zatelli et al., 2007). Celecoxib down-regulated the expression of the MRP1 protein in human lung cancer, which was accompanied by increased accumulation and enhanced cytotoxicity of doxorubicin (Kang et al., 2005). Ko et al. (2008) demonstrated that celecoxib reversed BCRP- and MRP1-related drug resistance via the down-regulation of MRP1 and BCRP mRNA in squamous cell carcinoma. Therefore COX-2 may play an important role in up-regulatimg the expression of MDR1/P-gp, MRP1 and BCRP via the COX-2/PGE2/EP4/PI3K pathway. In addition, COX-2 inhibitors can reverse the effects of COX-2. However, further research is still needed to clarify the mechanism by which COX-2 inhibitors regulate the transcription of the MDR.
In the present review, we have tried to describe the role of COX-2 in the regulation of MDR. COX-2 expression and the abundance of its enzymatic product PGE2 play key roles in the development of cancer. The activation of the COX-2/PGE2/EP signalling pathway can up-regulate the expression of all three ABC transporters, MDR1/P-gp, MRP1 and BCRP, which encode efflux pumps and play important roles in the development of multidrug resistance. COX inhibitors can sensitize cancers to chemotherapeutic drugs via inhibiting P-gp, MRP1 and BCRP, thus enhancing the cytotoxicity of anticancer drugs. Therefore we can use COX inhibitors to potentialize the effects of chemotherapeutic agents and reverse MDR.
Work in the authors laboratory received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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Received 21 June 2009/14 August 2009; accepted 16 September 2009
Published online 16 December 2009, doi:10.1042/CBI20090129
© 2010 The Author(s) Journal compilation. © 2010 Portland Press Ltd