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Caveolin-1 and cancer multidrug resistance: coordinate regulation of pro-survival proteins?
Leukemia Research 28 (2004) 907–908
Guest Editorial
Caveolin-1 and cancer multidrug resistance: coordinate regulation of pro-survival proteins?夽
Nearly three decades after the identification of the first drug transporter P-glycoprotein (P-gp) [1], cancer multidrug resistance (MDR) continues to challenge researchers trying to untangle its molecular basis, and to thwart oncologists attempting to cure cancer patients [2]. One of the important insights gained over the years is that in addition to overexpression of MDR transporters, MDR often involves additional mechanisms, prominent among which is the regulation of cellular apoptosis and survival pathways. In a previous issue, Kwong and co-workers reported that expression of P-gp, product of the MDR1 gene, and of caveolin-1, a putative pro-survival protein, in leukemic cells are highly correlated [3]. This report raises the intriguing possibility that the emergence of different MDR mechanisms may be coordinately regulated. Caveolin-1 is an essential protein constituent of plasma membrane caveolae, which are non-clathrin-coated, flask-shaped invaginations of the plasma membrane [4]. Caveolin-1 is a principal component of the caveolar coat and a regulator of caveolae-dependent signaling and endocytosis. In addition, caveolin-1 exhibits an unusual ability to interact with and modulate multiple signaling pathways. The interaction of caveolin-1 with other proteins occurs via a ‘scaffolding’ domain that binds short sequence motifs, such as xxxxxx (where is an aromatic amino acid) [5]. The ability of caveolin-1 to modulate signal transduction indicated that its expression is likely to profoundly affect cell function and cell fate. Indeed, the expression of caveolin-1 is tightly controlled: it is up regulated in terminally differentiated epithelial cells and, conversely, is down regulated upon oncogenic transformation. These and other results led to the suggestion that caveolin-1 is a tumor-suppressor protein [6]. However, this idea was inconsistent with the fact that caveolin-1 is highly expressed in some cancer cells, including mouse metastatic prostate cancer [7] and human multidrug resistant colon cancer cells [8]. In fact, a large body of data that has since accumulated reveals that there are major, divergent changes in caveolin-1 expression in human cancer cell lines and tumor 夽
doi of original article 10.1016/j.leukres.2004.01.010.
0145-2126/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2004.03.013
specimens, that depend on the type of cancer and on the tumor cell grade and progression stage [9]. In some forms of cancer caveolin-1 expression is down regulated, but in many other cancers caveolin-1 levels are high. The expression of caveolin-1 is positively correlated with the tumor’s cell grade and its progression stage and, in some cases, the expression of caveolin-1 was shown to be an independent predictor of poor disease prognosis. The relationship of caveolin-1 with MDR is multifaceted. As mentioned above, caveolin-1 is up regulated in numerous human MDR cancer cells [8,10–12]. P-gp, the prototypical MDR transporter, is often overexpressed in multidrug resistant cells, usually accompanied by other changes that affect drug metabolism and/or drug response [2]. P-gp is partially co-localized with caveolin-1 in lipid rafts as shown by sucrose gradient fractionation [8,13,14]. P-gp can also be co-immunoprecipitated with caveolin-1 in drug resistant cancer cells as well as in bovine brain capillary endothelial cells co-cultured with astrocytes, representing a model of blood brain barrier [13,15]. Together, the data suggest a physical interaction between these two proteins that may be mediated by a caveolin-1-binding motif in the N-terminal portion of P-gp (37-FSMFRYSNW-45). On the basis of these data, Kwong and co-workers hypothesized that caveolin-1 and MDR1 genes may be functionally related and therefore could be coordinately regulated [3]. Their retrospective study documents caveolin-1 and MDR1 gene expression in normal and acute myeloid leukemia (AML) bone marrow at diagnosis, at relapse and during regeneration, by means of quantitative real time polymerase chain reaction. A highly significant positive correlation was found between caveolin-1 and MDR1 mRNA levels in all tissue samples, indirectly supporting the idea that the two proteins are functionally related. In addition, the authors proposed that the observed correlation may explain the poor prognosis associated with up regulation of caveolin-1 in tumor samples [3]. The data of Kwong and co-workers highlight a more general question: Why is a putative tumor-suppressor protein like caveolin-1 expressed in so many cancer cells? Overexpression and gene-specific suppression studies leave little doubt that caveolin-1 has anti-proliferative actions in normal
908
Guest Editorial / Leukemia Research 28 (2004) 907–908
cells. Furthermore, genetic knockout of caveolin-1 results in tissue-specific hyperplasia and increased sensitivity to carcinogenic stimuli (although there is no evidence of spontaneous tumorigenesis) [16,17]. However, this begs the question of caveolin-1 function(s) in advanced stage/high grade, metastatic and multidrug resistant cancer cells, in which its expression is maintained or is up regulated. One possibility is that in such cells caveolin-1 promotes cancer cell survival and this hypothesis is consistent with some recent work [18–20]. However, the mechanisms whereby caveolin-1 affects cancer cell survival are still quite poorly understood. Be that as it may, the ability of caveolin-1 to effect both growth-inhibitory and survival-promoting actions may explain its divergent expression in human cancers. It may be hypothesized that, at early stages of cancer progression, expression of caveolin-1 is down regulated to suppress its growth inhibitory actions. Conversely, at later stages of the disease when the metastatic and drug resistant phenotypes are prevalent, expression of caveolin-1 is up regulated, reflecting its pro-survival actions. Clearly, much remains to be done to achieve a better understanding of the impact of caveolin-1 on human cancer cell phenotype, the mechanisms involved and its possible link to progression of the disease. References [1] Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455:152. [2] Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48. [3] Pang A, Wing Y, Kwong YL, Caveolin-1 gene is coordinately regulated with the multidrug resistance 1 gene in normal and leukemic bone marrow. Leukemia Res 2004;28:973–7. [4] Razani B, Woodman SE, Lisanti MP. Caveolae: from cell biology to animal physiology. Pharmacol Rev 2002;54:431. [5] Liu P, Rudick M, Anderson RG. Multiple functions of caveolin-1. J Biol Chem 2002;277:41295. [6] Razani B, Schlegel A, Liu J, Lisanti MP. Caveolin-1, a putative tumour suppressor gene. Biochem Soc Trans 2001;29:494. [7] Yang G, Truong LD, Timme TL, Ren C, Wheeler TM, Park SH, et al. Elevated expression of caveolin is associated with prostate and breast cancer. Clin Cancer Res 1998;4:1873. [8] Lavie Y, Fiucci G, Liscovitch M. Up-regulation of caveolae and caveolar constituents in multidrug-resistant cancer cells. J Biol Chem 1998;273:32380. [9] Liscovitch M, Burgermeister E, Jain N, Ravid D, Shatz M, Tencer L, Caveolin and cancer: a complex relationship. In: Mattson MP, editor. Membrane microdomain signaling: lipid rafts in biology and medicine. Totowa, New Jersey: Humana Press; 2004 [in press].
[10] Yang C-PH, Galbiati F, Volonte D, Horwitz SB, Lisanti MP. Upregulation of caveolin-1 and caveolae organelles in Taxol-resistant A549 cells. FEBS Lett 1998;439:368. [11] Bender FC, Reymond MA, Bron C, Quest AF. Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity. Cancer Res 2000;60:5870. [12] Belanger MM, Roussel E, Couet J. Up-regulation of caveolin expression by cytotoxic agents in drug-sensitive cancer cells. Anticancer Drugs 2003;14:281. [13] Demeule M, Jodoin J, Gingras D, Beliveau R. P-glycoprotein is localized in caveolae in resistant cells and in brain capillaries. FEBS Lett 2000;466:219. [14] Luker GD, Pica CM, Kumar AS, Covey DF, Piwnica-Worms D. Effects of cholesterol and enantiomeric cholesterol on P-glycoprotein localization and function in low-density membrane domains. Biochemistry 2000;39:7651. [15] Jodoin J, Demeule M, Fenart L, Cecchelli R, Farmer S, Linton KJ, et al. P-glycoprotein in blood-brain barrier endothelial cells: interaction and oligomerization with caveolins. J Neurochem 2003;87:1010. [16] Capozza F, Williams TM, Schubert W, McClain S, Bouzahzah B, Sotgia F, et al. Absence of caveolin-1 sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumor formation. Am J Pathol 2003;162:2029. [17] Williams TM, Cheung MW, Park DS, Razani B, Cohen AW, Muller WJ, et al. Loss of caveolin-1 gene expression accelerates the development of dysplastic mammary lesions in tumor-prone transgenic mice. Mol Biol Cell 2003;14:1027. [18] Fiucci G, Ravid D, Reich R, Liscovitch M. Caveolin-1 inhibits anchorage-independent growth, anoikis and invasiveness in MCF-7 human breast cancer cells. Oncogene 2002;21:2365. [19] Podar K, Tai YT, Cole CE, Hideshima T, Sattler M, Hamblin A, et al. Essential role of caveolae in interleukin-6- and insulin-like growth factor I-triggered Akt-1-mediated survival of multiple myeloma cells. J Biol Chem 2003;278:5794. [20] Li L, Ren CH, Tahir SA, Ren C, Thompson TC. Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 2003;23: 9389.
Maria Shatz Mordechai Liscovitch∗ Department of Biological Regulation Weizmann Institute of Science Rehovot 76100, Israel ∗ Corresponding author. Tel.: +972-8-934-2773 fax: +972-8-9344116 E-mail address: [email protected] (M. Liscovitch) 18 March 2004 Available online 7 June 2004
Guest Editorial
Caveolin-1 and cancer multidrug resistance: coordinate regulation of pro-survival proteins?夽
Nearly three decades after the identification of the first drug transporter P-glycoprotein (P-gp) [1], cancer multidrug resistance (MDR) continues to challenge researchers trying to untangle its molecular basis, and to thwart oncologists attempting to cure cancer patients [2]. One of the important insights gained over the years is that in addition to overexpression of MDR transporters, MDR often involves additional mechanisms, prominent among which is the regulation of cellular apoptosis and survival pathways. In a previous issue, Kwong and co-workers reported that expression of P-gp, product of the MDR1 gene, and of caveolin-1, a putative pro-survival protein, in leukemic cells are highly correlated [3]. This report raises the intriguing possibility that the emergence of different MDR mechanisms may be coordinately regulated. Caveolin-1 is an essential protein constituent of plasma membrane caveolae, which are non-clathrin-coated, flask-shaped invaginations of the plasma membrane [4]. Caveolin-1 is a principal component of the caveolar coat and a regulator of caveolae-dependent signaling and endocytosis. In addition, caveolin-1 exhibits an unusual ability to interact with and modulate multiple signaling pathways. The interaction of caveolin-1 with other proteins occurs via a ‘scaffolding’ domain that binds short sequence motifs, such as xxxxxx (where is an aromatic amino acid) [5]. The ability of caveolin-1 to modulate signal transduction indicated that its expression is likely to profoundly affect cell function and cell fate. Indeed, the expression of caveolin-1 is tightly controlled: it is up regulated in terminally differentiated epithelial cells and, conversely, is down regulated upon oncogenic transformation. These and other results led to the suggestion that caveolin-1 is a tumor-suppressor protein [6]. However, this idea was inconsistent with the fact that caveolin-1 is highly expressed in some cancer cells, including mouse metastatic prostate cancer [7] and human multidrug resistant colon cancer cells [8]. In fact, a large body of data that has since accumulated reveals that there are major, divergent changes in caveolin-1 expression in human cancer cell lines and tumor 夽
doi of original article 10.1016/j.leukres.2004.01.010.
0145-2126/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2004.03.013
specimens, that depend on the type of cancer and on the tumor cell grade and progression stage [9]. In some forms of cancer caveolin-1 expression is down regulated, but in many other cancers caveolin-1 levels are high. The expression of caveolin-1 is positively correlated with the tumor’s cell grade and its progression stage and, in some cases, the expression of caveolin-1 was shown to be an independent predictor of poor disease prognosis. The relationship of caveolin-1 with MDR is multifaceted. As mentioned above, caveolin-1 is up regulated in numerous human MDR cancer cells [8,10–12]. P-gp, the prototypical MDR transporter, is often overexpressed in multidrug resistant cells, usually accompanied by other changes that affect drug metabolism and/or drug response [2]. P-gp is partially co-localized with caveolin-1 in lipid rafts as shown by sucrose gradient fractionation [8,13,14]. P-gp can also be co-immunoprecipitated with caveolin-1 in drug resistant cancer cells as well as in bovine brain capillary endothelial cells co-cultured with astrocytes, representing a model of blood brain barrier [13,15]. Together, the data suggest a physical interaction between these two proteins that may be mediated by a caveolin-1-binding motif in the N-terminal portion of P-gp (37-FSMFRYSNW-45). On the basis of these data, Kwong and co-workers hypothesized that caveolin-1 and MDR1 genes may be functionally related and therefore could be coordinately regulated [3]. Their retrospective study documents caveolin-1 and MDR1 gene expression in normal and acute myeloid leukemia (AML) bone marrow at diagnosis, at relapse and during regeneration, by means of quantitative real time polymerase chain reaction. A highly significant positive correlation was found between caveolin-1 and MDR1 mRNA levels in all tissue samples, indirectly supporting the idea that the two proteins are functionally related. In addition, the authors proposed that the observed correlation may explain the poor prognosis associated with up regulation of caveolin-1 in tumor samples [3]. The data of Kwong and co-workers highlight a more general question: Why is a putative tumor-suppressor protein like caveolin-1 expressed in so many cancer cells? Overexpression and gene-specific suppression studies leave little doubt that caveolin-1 has anti-proliferative actions in normal
908
Guest Editorial / Leukemia Research 28 (2004) 907–908
cells. Furthermore, genetic knockout of caveolin-1 results in tissue-specific hyperplasia and increased sensitivity to carcinogenic stimuli (although there is no evidence of spontaneous tumorigenesis) [16,17]. However, this begs the question of caveolin-1 function(s) in advanced stage/high grade, metastatic and multidrug resistant cancer cells, in which its expression is maintained or is up regulated. One possibility is that in such cells caveolin-1 promotes cancer cell survival and this hypothesis is consistent with some recent work [18–20]. However, the mechanisms whereby caveolin-1 affects cancer cell survival are still quite poorly understood. Be that as it may, the ability of caveolin-1 to effect both growth-inhibitory and survival-promoting actions may explain its divergent expression in human cancers. It may be hypothesized that, at early stages of cancer progression, expression of caveolin-1 is down regulated to suppress its growth inhibitory actions. Conversely, at later stages of the disease when the metastatic and drug resistant phenotypes are prevalent, expression of caveolin-1 is up regulated, reflecting its pro-survival actions. Clearly, much remains to be done to achieve a better understanding of the impact of caveolin-1 on human cancer cell phenotype, the mechanisms involved and its possible link to progression of the disease. References [1] Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455:152. [2] Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002;2:48. [3] Pang A, Wing Y, Kwong YL, Caveolin-1 gene is coordinately regulated with the multidrug resistance 1 gene in normal and leukemic bone marrow. Leukemia Res 2004;28:973–7. [4] Razani B, Woodman SE, Lisanti MP. Caveolae: from cell biology to animal physiology. Pharmacol Rev 2002;54:431. [5] Liu P, Rudick M, Anderson RG. Multiple functions of caveolin-1. J Biol Chem 2002;277:41295. [6] Razani B, Schlegel A, Liu J, Lisanti MP. Caveolin-1, a putative tumour suppressor gene. Biochem Soc Trans 2001;29:494. [7] Yang G, Truong LD, Timme TL, Ren C, Wheeler TM, Park SH, et al. Elevated expression of caveolin is associated with prostate and breast cancer. Clin Cancer Res 1998;4:1873. [8] Lavie Y, Fiucci G, Liscovitch M. Up-regulation of caveolae and caveolar constituents in multidrug-resistant cancer cells. J Biol Chem 1998;273:32380. [9] Liscovitch M, Burgermeister E, Jain N, Ravid D, Shatz M, Tencer L, Caveolin and cancer: a complex relationship. In: Mattson MP, editor. Membrane microdomain signaling: lipid rafts in biology and medicine. Totowa, New Jersey: Humana Press; 2004 [in press].
[10] Yang C-PH, Galbiati F, Volonte D, Horwitz SB, Lisanti MP. Upregulation of caveolin-1 and caveolae organelles in Taxol-resistant A549 cells. FEBS Lett 1998;439:368. [11] Bender FC, Reymond MA, Bron C, Quest AF. Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity. Cancer Res 2000;60:5870. [12] Belanger MM, Roussel E, Couet J. Up-regulation of caveolin expression by cytotoxic agents in drug-sensitive cancer cells. Anticancer Drugs 2003;14:281. [13] Demeule M, Jodoin J, Gingras D, Beliveau R. P-glycoprotein is localized in caveolae in resistant cells and in brain capillaries. FEBS Lett 2000;466:219. [14] Luker GD, Pica CM, Kumar AS, Covey DF, Piwnica-Worms D. Effects of cholesterol and enantiomeric cholesterol on P-glycoprotein localization and function in low-density membrane domains. Biochemistry 2000;39:7651. [15] Jodoin J, Demeule M, Fenart L, Cecchelli R, Farmer S, Linton KJ, et al. P-glycoprotein in blood-brain barrier endothelial cells: interaction and oligomerization with caveolins. J Neurochem 2003;87:1010. [16] Capozza F, Williams TM, Schubert W, McClain S, Bouzahzah B, Sotgia F, et al. Absence of caveolin-1 sensitizes mouse skin to carcinogen-induced epidermal hyperplasia and tumor formation. Am J Pathol 2003;162:2029. [17] Williams TM, Cheung MW, Park DS, Razani B, Cohen AW, Muller WJ, et al. Loss of caveolin-1 gene expression accelerates the development of dysplastic mammary lesions in tumor-prone transgenic mice. Mol Biol Cell 2003;14:1027. [18] Fiucci G, Ravid D, Reich R, Liscovitch M. Caveolin-1 inhibits anchorage-independent growth, anoikis and invasiveness in MCF-7 human breast cancer cells. Oncogene 2002;21:2365. [19] Podar K, Tai YT, Cole CE, Hideshima T, Sattler M, Hamblin A, et al. Essential role of caveolae in interleukin-6- and insulin-like growth factor I-triggered Akt-1-mediated survival of multiple myeloma cells. J Biol Chem 2003;278:5794. [20] Li L, Ren CH, Tahir SA, Ren C, Thompson TC. Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 2003;23: 9389.
Maria Shatz Mordechai Liscovitch∗ Department of Biological Regulation Weizmann Institute of Science Rehovot 76100, Israel ∗ Corresponding author. Tel.: +972-8-934-2773 fax: +972-8-9344116 E-mail address: [email protected] (M. Liscovitch) 18 March 2004 Available online 7 June 2004