5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase

Hong-Tai Ji, Li-Ting Chien, Yu-Hsin Lin, Hsiung-Fei Chien, Chin-Tin Chen

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Photodynamic therapy (PDT) has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) signaling cascades are activated following 5-aminolevulinic acid (ALA)-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy. © 2010 Ji et al; licensee BioMed Central Ltd.
Original languageEnglish
JournalMolecular Cancer
Volume9
DOIs
Publication statusPublished - 2010
Externally publishedYes

Fingerprint

Aminolevulinic Acid
AMP-Activated Protein Kinases
Autophagy
Photochemotherapy
Cell Death
Photosensitizing Agents
Caspase Inhibitors
Caspase 9
Mitogen-Activated Protein Kinases
Caspase 3
Signal Transduction
Necrosis
Observation
Apoptosis
Light

Keywords

  • aminolevulinic acid
  • caspase 3
  • caspase 9
  • hydroxymethylglutaryl coenzyme A reductase kinase
  • mitogen activated protein kinase
  • mitogen activated protein kinase p38
  • stress activated protein kinase
  • adenylate kinase
  • photosensitizing agent
  • animal cell
  • article
  • autophagy
  • cancer cell
  • controlled study
  • DNA fragmentation
  • enzyme activation
  • human
  • human cell
  • mitochondrial membrane potential
  • nonhuman
  • oxidative stress
  • photodynamic therapy
  • survival rate
  • animal
  • drug effect
  • genetic transfection
  • immunoblotting
  • metabolism
  • methodology
  • mitochondrion
  • pathology
  • photochemotherapy
  • physiology
  • rat
  • signal transduction
  • Adenylate Kinase
  • Aminolevulinic Acid
  • Animals
  • Autophagy
  • DNA Fragmentation
  • Immunoblotting
  • MAP Kinase Signaling System
  • Membrane Potential, Mitochondrial
  • Mitochondria
  • Oxidative Stress
  • Photochemotherapy
  • Photosensitizing Agents
  • Rats
  • Signal Transduction
  • Transfection

Cite this

5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase. / Ji, Hong-Tai; Chien, Li-Ting; Lin, Yu-Hsin; Chien, Hsiung-Fei; Chen, Chin-Tin.

In: Molecular Cancer, Vol. 9, 2010.

Research output: Contribution to journalArticle

@article{e098ad447d56463a981f0226b2464f33,
title = "5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase",
abstract = "Photodynamic therapy (PDT) has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) signaling cascades are activated following 5-aminolevulinic acid (ALA)-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy. {\circledC} 2010 Ji et al; licensee BioMed Central Ltd.",
keywords = "aminolevulinic acid, caspase 3, caspase 9, hydroxymethylglutaryl coenzyme A reductase kinase, mitogen activated protein kinase, mitogen activated protein kinase p38, stress activated protein kinase, adenylate kinase, photosensitizing agent, animal cell, article, autophagy, cancer cell, controlled study, DNA fragmentation, enzyme activation, human, human cell, mitochondrial membrane potential, nonhuman, oxidative stress, photodynamic therapy, survival rate, animal, drug effect, genetic transfection, immunoblotting, metabolism, methodology, mitochondrion, pathology, photochemotherapy, physiology, rat, signal transduction, Adenylate Kinase, Aminolevulinic Acid, Animals, Autophagy, DNA Fragmentation, Immunoblotting, MAP Kinase Signaling System, Membrane Potential, Mitochondrial, Mitochondria, Oxidative Stress, Photochemotherapy, Photosensitizing Agents, Rats, Signal Transduction, Transfection",
author = "Hong-Tai Ji and Li-Ting Chien and Yu-Hsin Lin and Hsiung-Fei Chien and Chin-Tin Chen",
note = "被引用次數:24 Export Date: 16 March 2016 CODEN: MCOAC 通訊地址: Chen, C.-T.; Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan; 電子郵件: chintin@ntu.edu.tw 化學物質/CAS: aminolevulinic acid, 106-60-5; caspase 3, 169592-56-7; caspase 9, 180189-96-2; hydroxymethylglutaryl coenzyme A reductase kinase, 172522-01-9, 72060-32-3; mitogen activated protein kinase, 142243-02-5; stress activated protein kinase, 155215-87-5; adenylate kinase, 9013-02-9; Adenylate Kinase, 2.7.4.3; Aminolevulinic Acid, 106-60-5; Photosensitizing Agents 製造商: Sigma, United States 參考文獻: Dougherty, T.J., Gomer, C.J., Henderson, B.W., Jori, G., Kessel, D., Korbelik, M., Moan, J., Peng, Q., Photodynamic therapy (1998) J Natl Cancer Inst, 90, pp. 889-905. , 10.1093/jnci/90.12.889, 9637138; Dolmans, D.E., Fukumura, D., Jain, R.K., Photodynamic therapy for cancer (2003) Nat Rev Cancer, 3, pp. 380-387. , 10.1038/nrc1071, 12724736; Gomer, C.J., Rucker, N., Ferrario, A., Wong, S., Properties and applications of photodynamic therapy (1989) Radiat Res, 120, pp. 1-18. , 10.2307/3577632, 2678224; Almeida, R.D., Manadas, B.J., Carvalho, A.P., Duarte, C.B., Intracellular signaling mechanisms in photodynamic therapy (2004) Biochim Biophys Acta, 1704, pp. 59-86; Buytaert, E., Dewaele, M., Agostinis, P., Molecular effectors of multiple cell death pathways initiated by photodynamic therapy (2007) Biochim Biophys Acta, 1776, pp. 86-107; Gardner, L.C., Smith, S.J., Cox, T.M., Biosynthesis of delta-aminolevulinic acid and the regulation of heme formation by immature erythroid cells in man (1991) J Biol Chem, 266, pp. 22010-22018; Hardie, D.G., Carling, D., The AMP-activated protein kinase--fuel gauge of the mammalian cell? (1997) Eur J Biochem, 246, pp. 259-273. , 10.1111/j.1432-1033.1997.00259.x, 9208914; Kemp, B.E., Mitchelhill, K.I., Stapleton, D., Michell, B.J., Chen, Z.P., Witters, L.A., Dealing with energy demand: the AMP-activated protein kinase (1999) Trends Biochem Sci, 24, pp. 22-25. , 10.1016/S0968-0004(98)01340-1, 10087918; Hardie, D.G., Scott, J.W., Pan, D.A., Hudson, E.R., Management of cellular energy by the AMP-activated protein kinase system (2003) FEBS Lett, 546, pp. 113-120. , 10.1016/S0014-5793(03)00560-X, 12829246; Ramamurthy, S., Ronnett, G.V., Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain (2006) J Physiol, 574, pp. 85-93. , 10.1113/jphysiol.2006.110122, 1817796, 16690704; Blazquez, C., Geelen, M.J., Velasco, G., Guzman, M., The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes (2001) FEBS Lett, 489, pp. 149-153. , 10.1016/S0014-5793(01)02089-0, 11165240; Russell, R.R., Li, J., Coven, D.L., Pypaert, M., Zechner, C., Palmeri, M., Giordano, F.J., Young, L.H., AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury (2004) J Clin Invest, 114, pp. 495-503. , 503766, 15314686; Stefanelli, C., Stanic, I., Bonavita, F., Flamigni, F., Pignatti, C., Guarnieri, C., Caldarera, C.M., Inhibition of glucocorticoid-induced apoptosis with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMP-activated protein kinase (1998) Biochem Biophys Res Commun, 243, pp. 821-826. , 10.1006/bbrc.1998.8154, 9500985; Dagon, Y., Avraham, Y., Berry, E.M., AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes (2006) Biochem Biophys Res Commun, 340, pp. 43-47. , 10.1016/j.bbrc.2005.11.159, 16377306; Kefas, B.A., Cai, Y., Ling, Z., Heimberg, H., Hue, L., Pipeleers, D., Casteele, M., AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase (2003) J Mol Endocrinol, 30, pp. 151-161. , 10.1677/jme.0.0300151, 12683939; Meisse, D., Casteele, M., Beauloye, C., Hainault, I., Kefas, B.A., Rider, M.H., Foufelle, F., Hue, L., Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells (2002) FEBS Lett, 526, pp. 38-42. , 10.1016/S0014-5793(02)03110-1, 12208500; Liang, J., Shao, S.H., Xu, Z.X., Hennessy, B., Ding, Z., Larrea, M., Kondo, S., Walker, C.L., The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis (2007) Nat Cell Biol, 9, pp. 218-224. , 10.1038/ncb1537, 17237771; Meley, D., Bauvy, C., Houben-Weerts, J.H., Dubbelhuis, P.F., Helmond, M.T., Codogno, P., Meijer, A.J., AMP-activated protein kinase and the regulation of autophagic proteolysis (2006) J Biol Chem, 281, pp. 34870-34879. , 10.1074/jbc.M605488200, 16990266; Papandreou, I., Lim, A.L., Laderoute, K., Denko, N.C., Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L (2008) Cell Death Differ, 15, pp. 1572-1581. , 10.1038/cdd.2008.84, 18551130; Levine, B., Yuan, J., Autophagy in cell death: an innocent convict? (2005) J Clin Invest, 115, pp. 2679-2688. , 10.1172/JCI26390, 1236698, 16200202; Onodera, J., Ohsumi, Y., Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation (2005) J Biol Chem, 280, pp. 31582-31586. , 10.1074/jbc.M506736200, 16027116; Baehrecke, E.H., Autophagy: dual roles in life and death? (2005) Nat Rev Mol Cell Biol, 6, pp. 505-510. , 10.1038/nrm1666, 15928714; Oleinick, N.L., Morris, R.L., Belichenko, I., The role of apoptosis in response to photodynamic therapy: what, where, why, and how (2002) Photochem Photobiol Sci, 1, pp. 1-21. , 10.1039/b108586g, 12659143; Kessel, D., Vicente, M.G., Reiners, J.J., Initiation of apoptosis and autophagy by photodynamic therapy (2006) Lasers Surg Med, 38, pp. 482-488. , 10.1002/lsm.20334, 2749509, 16615135; Tsai, J.C., Wu, C.L., Chien, H.F., Chen, C.T., Reorganization of cytoskeleton induced by 5-aminolevulinic acid-mediated photodynamic therapy and its correlation with mitochondrial dysfunction (2005) Lasers Surg Med, 36, pp. 398-408. , 10.1002/lsm.20179, 15856508; Jin, S., Autophagy, mitochondrial quality control, and oncogenesis (2006) Autophagy, 2, pp. 80-84; Greene, L.A., Tischler, A.S., Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor (1976) Proc Natl Acad Sci USA, 73, pp. 2424-2428. , 10.1073/pnas.73.7.2424, 430592, 1065897; Yang, P.C., Luh, K.T., Wu, R., Wu, C.W., Characterization of the mucin differentiation in human lung adenocarcinoma cell lines (1992) Am J Respir Cell Mol Biol, 7, pp. 161-171; Ji, Z., Yang, G., Vasovic, V., Cunderlikova, B., Suo, Z., Nesland, J.M., Peng, Q., Subcellular localization pattern of protoporphyrin IX is an important determinant for its photodynamic efficiency of human carcinoma and normal cell lines (2006) J Photochem Photobiol B, 84, pp. 213-220. , 10.1016/j.jphotobiol.2006.03.006, 16709459; Tsai, T., Hong, R.L., Tsai, J.C., Lou, P.J., Ling, I.F., Chen, C.T., Effect of 5-aminolevulinic acid-mediated photodynamic therapy on MCF-7 and MCF-7/ADR cells (2004) Lasers Surg Med, 34, pp. 62-72. , 10.1002/lsm.10246, 14755426; Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Fujii, N., Role of AMP-activated protein kinase in mechanism of metformin action (2001) J Clin Invest, 108, pp. 1167-1174. , 209533, 11602624; Kessel, D., Luo, Y., Photodynamic therapy: a mitochondrial inducer of apoptosis (1999) Cell Death Differ, 6, pp. 28-35. , 10.1038/sj.cdd.4400446, 10200545; 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year = "2010",
doi = "10.1186/1476-4598-9-91",
language = "English",
volume = "9",
journal = "Molecular Cancer",
issn = "1476-4598",
publisher = "BioMed Central",

}

TY - JOUR

T1 - 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase

AU - Ji, Hong-Tai

AU - Chien, Li-Ting

AU - Lin, Yu-Hsin

AU - Chien, Hsiung-Fei

AU - Chen, Chin-Tin

N1 - 被引用次數:24 Export Date: 16 March 2016 CODEN: MCOAC 通訊地址: Chen, C.-T.; Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan; 電子郵件: chintin@ntu.edu.tw 化學物質/CAS: aminolevulinic acid, 106-60-5; caspase 3, 169592-56-7; caspase 9, 180189-96-2; hydroxymethylglutaryl coenzyme A reductase kinase, 172522-01-9, 72060-32-3; mitogen activated protein kinase, 142243-02-5; stress activated protein kinase, 155215-87-5; adenylate kinase, 9013-02-9; Adenylate Kinase, 2.7.4.3; Aminolevulinic Acid, 106-60-5; Photosensitizing Agents 製造商: Sigma, United States 參考文獻: Dougherty, T.J., Gomer, C.J., Henderson, B.W., Jori, G., Kessel, D., Korbelik, M., Moan, J., Peng, Q., Photodynamic therapy (1998) J Natl Cancer Inst, 90, pp. 889-905. , 10.1093/jnci/90.12.889, 9637138; Dolmans, D.E., Fukumura, D., Jain, R.K., Photodynamic therapy for cancer (2003) Nat Rev Cancer, 3, pp. 380-387. , 10.1038/nrc1071, 12724736; Gomer, C.J., Rucker, N., Ferrario, A., Wong, S., Properties and applications of photodynamic therapy (1989) Radiat Res, 120, pp. 1-18. , 10.2307/3577632, 2678224; Almeida, R.D., Manadas, B.J., Carvalho, A.P., Duarte, C.B., Intracellular signaling mechanisms in photodynamic therapy (2004) Biochim Biophys Acta, 1704, pp. 59-86; Buytaert, E., Dewaele, M., Agostinis, P., Molecular effectors of multiple cell death pathways initiated by photodynamic therapy (2007) Biochim Biophys Acta, 1776, pp. 86-107; Gardner, L.C., Smith, S.J., Cox, T.M., Biosynthesis of delta-aminolevulinic acid and the regulation of heme formation by immature erythroid cells in man (1991) J Biol Chem, 266, pp. 22010-22018; Hardie, D.G., Carling, D., The AMP-activated protein kinase--fuel gauge of the mammalian cell? (1997) Eur J Biochem, 246, pp. 259-273. , 10.1111/j.1432-1033.1997.00259.x, 9208914; Kemp, B.E., Mitchelhill, K.I., Stapleton, D., Michell, B.J., Chen, Z.P., Witters, L.A., Dealing with energy demand: the AMP-activated protein kinase (1999) Trends Biochem Sci, 24, pp. 22-25. , 10.1016/S0968-0004(98)01340-1, 10087918; Hardie, D.G., Scott, J.W., Pan, D.A., Hudson, E.R., Management of cellular energy by the AMP-activated protein kinase system (2003) FEBS Lett, 546, pp. 113-120. , 10.1016/S0014-5793(03)00560-X, 12829246; Ramamurthy, S., Ronnett, G.V., Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain (2006) J Physiol, 574, pp. 85-93. , 10.1113/jphysiol.2006.110122, 1817796, 16690704; Blazquez, C., Geelen, M.J., Velasco, G., Guzman, M., The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes (2001) FEBS Lett, 489, pp. 149-153. , 10.1016/S0014-5793(01)02089-0, 11165240; Russell, R.R., Li, J., Coven, D.L., Pypaert, M., Zechner, C., Palmeri, M., Giordano, F.J., Young, L.H., AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury (2004) J Clin Invest, 114, pp. 495-503. , 503766, 15314686; Stefanelli, C., Stanic, I., Bonavita, F., Flamigni, F., Pignatti, C., Guarnieri, C., Caldarera, C.M., Inhibition of glucocorticoid-induced apoptosis with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMP-activated protein kinase (1998) Biochem Biophys Res Commun, 243, pp. 821-826. , 10.1006/bbrc.1998.8154, 9500985; Dagon, Y., Avraham, Y., Berry, E.M., AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2alpha in adipocytes (2006) Biochem Biophys Res Commun, 340, pp. 43-47. , 10.1016/j.bbrc.2005.11.159, 16377306; Kefas, B.A., Cai, Y., Ling, Z., Heimberg, H., Hue, L., Pipeleers, D., Casteele, M., AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase (2003) J Mol Endocrinol, 30, pp. 151-161. , 10.1677/jme.0.0300151, 12683939; Meisse, D., Casteele, M., Beauloye, C., Hainault, I., Kefas, B.A., Rider, M.H., Foufelle, F., Hue, L., Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells (2002) FEBS Lett, 526, pp. 38-42. , 10.1016/S0014-5793(02)03110-1, 12208500; Liang, J., Shao, S.H., Xu, Z.X., Hennessy, B., Ding, Z., Larrea, M., Kondo, S., Walker, C.L., The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis (2007) Nat Cell Biol, 9, pp. 218-224. , 10.1038/ncb1537, 17237771; Meley, D., Bauvy, C., Houben-Weerts, J.H., Dubbelhuis, P.F., Helmond, M.T., Codogno, P., Meijer, A.J., AMP-activated protein kinase and the regulation of autophagic proteolysis (2006) J Biol Chem, 281, pp. 34870-34879. , 10.1074/jbc.M605488200, 16990266; Papandreou, I., Lim, A.L., Laderoute, K., Denko, N.C., Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L (2008) Cell Death Differ, 15, pp. 1572-1581. , 10.1038/cdd.2008.84, 18551130; Levine, B., Yuan, J., Autophagy in cell death: an innocent convict? (2005) J Clin Invest, 115, pp. 2679-2688. , 10.1172/JCI26390, 1236698, 16200202; Onodera, J., Ohsumi, Y., Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation (2005) J Biol Chem, 280, pp. 31582-31586. , 10.1074/jbc.M506736200, 16027116; Baehrecke, E.H., Autophagy: dual roles in life and death? (2005) Nat Rev Mol Cell Biol, 6, pp. 505-510. , 10.1038/nrm1666, 15928714; Oleinick, N.L., Morris, R.L., Belichenko, I., The role of apoptosis in response to photodynamic therapy: what, where, why, and how (2002) Photochem Photobiol Sci, 1, pp. 1-21. , 10.1039/b108586g, 12659143; Kessel, D., Vicente, M.G., Reiners, J.J., Initiation of apoptosis and autophagy by photodynamic therapy (2006) Lasers Surg Med, 38, pp. 482-488. , 10.1002/lsm.20334, 2749509, 16615135; Tsai, J.C., Wu, C.L., Chien, H.F., Chen, C.T., Reorganization of cytoskeleton induced by 5-aminolevulinic acid-mediated photodynamic therapy and its correlation with mitochondrial dysfunction (2005) Lasers Surg Med, 36, pp. 398-408. , 10.1002/lsm.20179, 15856508; Jin, S., Autophagy, mitochondrial quality control, and oncogenesis (2006) Autophagy, 2, pp. 80-84; Greene, L.A., Tischler, A.S., Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor (1976) Proc Natl Acad Sci USA, 73, pp. 2424-2428. , 10.1073/pnas.73.7.2424, 430592, 1065897; 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PY - 2010

Y1 - 2010

N2 - Photodynamic therapy (PDT) has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) signaling cascades are activated following 5-aminolevulinic acid (ALA)-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy. © 2010 Ji et al; licensee BioMed Central Ltd.

AB - Photodynamic therapy (PDT) has been developed as an anticancer treatment, which is based on the tumor-specific accumulation of a photosensitizer that induces cell death after irradiation of light with a specific wavelength. Depending on the subcellular localization of the photosensitizer, PDT could trigger various signal transduction cascades and induce cell death such as apoptosis, autophagy, and necrosis. In this study, we report that both AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase (MAPK) signaling cascades are activated following 5-aminolevulinic acid (ALA)-mediated PDT in both PC12 and CL1-0 cells. Although the activities of caspase-9 and -3 are elevated, the caspase inhibitor zVAD-fmk did not protect cells against ALA-PDT-induced cell death. Instead, autophagic cell death was found in PC12 and CL1-0 cells treated with ALA-PDT. Most importantly, we report here for the first time that it is the activation of AMPK, but not MAPKs that plays a crucial role in mediating autophagic cell death induced by ALA-PDT. This novel observation indicates that the AMPK pathway play an important role in ALA-PDT-induced autophagy. © 2010 Ji et al; licensee BioMed Central Ltd.

KW - aminolevulinic acid

KW - caspase 3

KW - caspase 9

KW - hydroxymethylglutaryl coenzyme A reductase kinase

KW - mitogen activated protein kinase

KW - mitogen activated protein kinase p38

KW - stress activated protein kinase

KW - adenylate kinase

KW - photosensitizing agent

KW - animal cell

KW - article

KW - autophagy

KW - cancer cell

KW - controlled study

KW - DNA fragmentation

KW - enzyme activation

KW - human

KW - human cell

KW - mitochondrial membrane potential

KW - nonhuman

KW - oxidative stress

KW - photodynamic therapy

KW - survival rate

KW - animal

KW - drug effect

KW - genetic transfection

KW - immunoblotting

KW - metabolism

KW - methodology

KW - mitochondrion

KW - pathology

KW - photochemotherapy

KW - physiology

KW - rat

KW - signal transduction

KW - Adenylate Kinase

KW - Aminolevulinic Acid

KW - Animals

KW - Autophagy

KW - DNA Fragmentation

KW - Immunoblotting

KW - MAP Kinase Signaling System

KW - Membrane Potential, Mitochondrial

KW - Mitochondria

KW - Oxidative Stress

KW - Photochemotherapy

KW - Photosensitizing Agents

KW - Rats

KW - Signal Transduction

KW - Transfection

U2 - 10.1186/1476-4598-9-91

DO - 10.1186/1476-4598-9-91

M3 - Article

VL - 9

JO - Molecular Cancer

JF - Molecular Cancer

SN - 1476-4598

ER -