👤 R.T. Bronson

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Role of AMPK in Regulation of Oxaliplatin-Resistant Human Colorectal Cancer

Y. Park, P. Xu, D.M. Parkin +324 more · 2022 · Biomedicines · MDPI · added 2026-04-20
Y. Park, P. Xu, D.M. Parkin, F. Bray, J. Ferlay, P. Pisani, N. Andre, W. Schmiegel, B. Gustavsson, G. Carlsson, D. Machover, N. Petrelli, A. Roth, H. Schmoll, K. Tveit, F. Gibson, G. Housman, S. Byler, S. Heerboth, K. Lapinska, M. Longacre, N. Snyder, S. Sarkar, L. Bao, S. Hazari, S. Mehra, D. Kaushal, K. Moroz, S. Dash, Z. Yuan, X. Shi, Y. Qi, T. Jia, X. Yuan, Y. Zou, C. Liu, H. Yu, Y. Yuan, X. He, A.K. Pandurangan, D. Chao, W. Jiao, C. Yin, N. Jianyun, C. Ceshi, A. Guerrero-Zotano, I.A. Mayer, C.L. Arteaga, C. Han, G. Xing, M. Zhang, M. Zhong, Z. Han, C. He, X. Liu, Z. Zou, T. Tao, H. Li, X. Zhu, D.D. Sarbassov, S.M. Ali, D.M. Sabatini, D. Heras-Sandoval, J.M. Pérez-Rojas, J. Hernández-Damián, J. Pedraza-Chaverri, J. Roper, M.P. Richardson, W.V. Wang, L.G. Richard, W. Chen, E.M. Coffee, M.J. Sinnamon, L. Lee, P. Chen, R.T. Bronson, Y. Kondo, T. Kanzawa, R. Sawaya, S. Kondo, W. Li, Y. Zhou, J. Yang, H. Zhang, P. Zheng, Z. Wang, N. Wang, P. Liu, X. Xie, D. Zhang, W. Wang, X. Sun, D. Xu, C. Wang, Q. Zhang, H. Wang, W. Luo, Y. Chen, H. Chen, Z. Cao, Y. Yang, S. Yu, Y. Li, J. Huang, L. Xiong, S. Lei, C. Peng, M.G. Vander Heiden, L.C. Cantley, C.B. Thompson, D.H. Suh, M.A. Kim, H. Kim, M. Kim, H.S. Kim, H.H. Chung, Y. Kim, Y.S. Song, J. Peng, Y. Cui, S. Xu, X. Wu, Y. Huang, W. Zhou, S. Wang, Z. Fu, H. Xie, G. Wang, Y. Yu, Y.Z. Wang, P.H. Yin, K. Xu, H. Bleiberg, P. Perego, J. Robert, W. Lian, M. Li, R.N. Seetharam, A. Sood, S. Goel, E. Martinez-Balibrea, A. Martínez-Cardús, A. Ginés, V. Ruiz de Porras, C. Moutinho, L. Layos, J.L. Manzano, C. Bugés, S. Bystrup, M. Esteller, P. Noordhuis, A.C. Laan, K. Van de Born, R.J. Honeywell, G.J. Peters, W. Sun, Y. Ge, J. Cui, B. Liu, W. Lu, M. Ma, Q. Yan, W. He, Y. Hu, L. Xia, W. Hou, J. Chai, H. Guo, J. Yu, S.H. Bae, J.H. Park, H.G. Choi, S.H. Kim, H.Y. Yoo, S.Y. Park, S.Y. Chang, G. Meyer, A. Czompa, C. Reboul, E. Stepania, A. Czegledi, I. Bak, G. Balla, J. Balla, A. Tosaki, I. Lekli, W. Cao, J. Li, K. Yang, D. Cao, I. Tanida, T. Ueno, E. Kominami, J.M. Woynarowski, S. Faivre, M.C. Herzig, B. Arnett, W.G. Chapman, A.V. Trevino, E. Raymond, S.G. Chaney, A. Vaisman, M. Varchenko, R. Teng, J. Zhou, B. Seifer, J. Shen, L. Wang, H.R. Kang, C.K. Jeon, S. Lim, J.I. Barrasa, A. Santiago-Gómez, N. Olmo, M.A. Lizarbe, J. Turnay, A. Derjuga, C. Richard, M. Crosato, P.S. Wright, L. Chalifour, J. Valdez, A. Barraso, H.A. Crissman, W. Nishioka, E.M. Bradbury, Q. Shi, S. Li, L. Jin, H. Lai, Y. Wu, Z. Cai, M. Zhu, Q. Li, C.W. Yao, K.A. Kang, M.J. Piao, Y.S. Ryu, P.M.D.J. Fernando, M.C. Oh, J.E. Park, K. Shilnikova, S.-Y. Na, S.U. Jeong, Y. Zhao, X. Hu, Y. Liu, S. Dong, Z. Wen, S. Zhang, Q. Huang, M. Shi, V.G.A. Arciuch, M.A. Russo, K.S. Kang, A.D. Cristofano, L. Vucicevic, M. Misirkic, J. Kristina, U. Vilimanovich, E. Sudar, E. Isenovic, M. Prica, L. Harhaji-Trajkovic, T. Kravic-Stevovic, B. Vladimir, S. Lee, W. Yang, D.K. Kim, M. Shin, K.U. Choi, D.S. Suh, Y.H. Kim, T.-H. Hwang, J.H. Kim, C. Wu, Y. Chao, S. Shiah, W. Lin, M. Mouradian, K.D. Kikawa, B.P. Dranka, S.M. Komas, B. Kalyanaraman, R.S. Pardini, F. Gharibpoor, S.K. Zonouzi, S. Razi, H. Rezaei, Z. Yao, F. Xie, Z. Liang, W. Xu, H. Zhou, L.-H. Qu, D. Catanzaro, D. Gabbia, V. Cocetta, M. Biagi, E. Ragazzi, M. Montopoli, M. Carrara, X. Cao, L. Fang, S. Gibbs, Z. Dai, P. Wen, X. Zheng, W. Sadee, D. Sun, E.E. Mendoza, M.G. Pocceschi, X. Kong, D.B. Leeper, J. Caro, K.H. Limesand, R. Burd, E. Domenech, C. Maestre, L. Esteban-Martínez, D. Partida, R. Pascual, G. Fernandez-Miranda, E. Seco, R. Campos-Olivas, M. Perez, D. Megias Show less
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In Show more
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC 50 ) of oxaliplatin were 4.40–12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs. Show less
đź“„ PDF DOI: 10.3390/biomedicines10112690
Pt amino-acid anticancer

Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A

T. Narayan, A. Dutta, A. Agarwal +541 more · 2022 · iScience · Elsevier · added 2026-04-20
T. Narayan, A. Dutta, A. Agarwal, R.J. MacKenzie, R. Pippa, C.A. Eide, J. Oddo, J.W. Tyner, R. Sears, M.P. Vitek, M.D. Odero, D.J. Christensen, B.J. Druker, A. Ashkenazi, R.C. Pai, S. Fong, S. Leung, D.A. Lawrence, S.A. Marsters, C. Blackie, L. Chang, A.E. McMurtrey, A. Hebert, A. Bene, T.C. Chambers, I. Beuvink, A. Boulay, S. Fumagalli, F. Zilbermann, S. Ruetz, T. O'Reilly, F. Natt, J. Hall, H.A. Lane, G. Thomas, M. Bhat, N. Robichaud, L. Hulea, N. Sonenberg, J. Pelletier, I. Topisirovic, R. Briffa, S.P. Langdon, G. Grech, D.J. Harrison, B.A. Carneiro, W.S. El-Deiry, T.C. Chou, A.E. Collier, D.F. Spandau, R.C. Wek, I. Cristobal, R. Manso, R. Rincón, C. Caramés, C. Senin, A. Borrero, J. Martínez-Useros, M. Rodriguez, S. Zazo, O. Aguilera, R. Rincon, C. Carames, J. Madoz-Gurpide, F. Rojo, J. Garcia-Foncillas, R.M. De Palma, S.R. Parnham, Y. Li, J.J. Oaks, Y.K. Peterson, Z.M. Szulc, B.M. Roth, Y. Xing, B. Ogretmen, D. Deng, K. Shah, M.J. Fournier, L. Coudert, S. Mellaoui, P. Adjibade, C. Gareau, M.F. Côté, R.C. Gaudreault, R. Mazroui, A.M. Gaben, C. Saucier, M. Bedin, V. Barbu, J. Mester, C. Filion, D. Martel, Y. Labelle, A.G. Georgakilas, O.A. Martin, W.M. Bonner, M.J. Gerdes, C.J. Sevinsky, A. Sood, S. Adak, M.O. Bello, A. Bordwell, A. Can, A. Corwin, S. Dinn, R.J. Filkins, M. Gorospe, X. Wang, K.Z. Guyton, N.J. Holbrook, M.M. Gottesman, J.R. Graff, B.W. Konicek, J.H. Carter, E.G. Marcusson, R.S. Herbst, S.G. Eckhardt, R. Kurzrock, S. Ebbinghaus, P.J. O'Dwyer, M.S. Gordon, W. Novotny, M.A. Goldwasser, T.M. Tohnya, B.L. Lum, S.D. Heys, K.G. Park, M.A. McNurlan, A.G. Calder, V. Buchan, K. Blessing, O. Eremin, P.J. Garlick, B. Hoang, A. Benavides, Y. Shi, Y. Yang, P. Frost, J. Gera, A. Lichtenstein, A.N. Hobden, E. Cundliffe, N. Ikoma, K. Raghav, G. Chang, A. Ishitsuka, E. Fujine, Y. Mizutani, C. Tawada, H. Kanoh, Y. Banno, M. Seishima, S. Iwasaki, N.T. Ingolia, S.C. Jahn, P.E. Corsino, B.J. Davis, M.E. Law, P. Nørgaard, B.K. Law, V. Janssens, S. Longin, J. Goris, M.A. Jensen, V. Ferretti, R.L. Grossman, L.M. Staudt, Y.H. Jin, K.J. Yoo, Y.H. Lee, S.K. Lee, A. Kahvejian, Y.V. Svitkin, R. Sukarieh, M.N. M'Boutchou, S.K. Kelley, L.A. Harris, D. Xie, L. Deforge, K. Totpal, J. Bussiere, J.A. Fox, S.L. Kim, Y.C. Liu, Y.R. Park, S.Y. Seo, S.H. Kim, I.H. Kim, S.O. Lee, S.T. Lee, D.G. Kim, S.W. Kim, N.N. Kreis, F. Louwen, J. Yuan, M. Law, E. Forrester, A. Chytil, P. Corsino, G. Green, B. Davis, T. Rowe, B. Law, S.L. Lehman, G.J. Cerniglia, G.J. Johannes, J. Ye, S. Ryeom, C. Koumenis, S. Lek, J. Vargas-Medrano, E. Villanueva, B. Marcus, W. Godfrey, R.G. Perez, J. Lemke, S. von Karstedt, J. Zinngrebe, H. Walczak, D. Leonard, W. Huang, S. Izadmehr, C.M. O'Connor, D.D. Wiredja, Z. Wang, N. Zaware, Y. Chen, D.M. Schlatzer, J. Kiselar, V. Leung-Pineda, C.E. Ryan, H. Piwnica-Worms, L. Li, J. Wang, J.G. Li, Z. Wu, P. Ma, X.J. Lian, I.E. Gallouzi, H. Lin, X. Qiu, B. Zhang, J. Zhang, T.A. Lin, X. Kong, T.A.J. Haystead, A. Pause, G. Belsham, J.C. Lawrence, J. Lu, J.S. Kovach, F. Johnson, J. Chiang, R. Hodes, R. Lonser, Z. Zhuang, M. Mahyar-Roemer, K. Roemer, A. Maiuthed, C. Ninsontia, K. Erlenbach-Wuensch, B. Ndreshkjana, J.K. Muenzner, A. Caliskan, H. Ahmed P, A.P. Husayn, C. Chaotham, A. Hartmann, K. Malinowsky, U. Nitsche, K.P. Janssen, F.G. Bader, C. Spath, E. Drecoll, G. Keller, H. Hofler, S. Mazhar, S.E. Taylor, J. Sangodkar, G. Narla, K. McClinch, R.A. Avelar, D. Callejas, D. Wiredja, A. Perl, D.B. Kastrinsky, D. Schlatzer, M. Cooper, D.R. McIlwain, T. Berger, T.W. Mak, N. Melling, R. Simon, J.R. Izbicki, L.M. Terracciano, C. Bokemeyer, G. Sauter, A.H. Marx, J.R. Mills, Y. Hippo, F. Robert, S.M.H. Chen, A. Malina, C.J. Lin, U. Trojahn, H.G. Wendel, A. Charest, R.T. Bronson, C.S. Mitsiades, S.P. Treon, N. Mitsiades, Y. Shima, P. Richardson, R. Schlossman, T. Hideshima, K.C. Anderson, K. Morita, S. He, R.P. Nowak, M.W. Zimmerman, C. Fu, A.D. Durbin, M.W. Martel, N. Prutsch, N.S. Gray, S. Narayan, A.S. Jaiswal, R. Sharma, A. Nawab, L.V. Duckworth, M. Zajac-Kaye, T.J. George, J. Sharma, A.K. Sharma, R.A. Hromas, S. Ramisetti, A. Singh-Pillay, P. Singh, S. Amin, P. Palaiologos, D. Chrysikos, S. Theocharis, G. Kouraklis, G.J. Belsham, A.C. Gingras, O. Donzé, M.D. Ralff, P.G. Richardson, C. Eng, J. Kolesar, N.R. Rodrigues, A. Rowan, M.E. Smith, I.B. Kerr, W.F. Bodmer, J.V. Gannon, D.P. Lane, H.K. Roy, B.F. Olusola, D.L. Clemens, W.J. Karolski, A. Ratashak, H.T. Lynch, T.C. Smyrk, E. Rozengurt, H.P. Soares, J. Sinnet-Smith, P.P. Ruvolo, R. Tohme, E.K. Schmidt, G. Clavarino, M. Ceppi, P. Pierre, R.R. Sharma, T.S. Ravikumar, D. Raimo, W.L. Yang, R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal, J.C. Soria, Z. Márk, P. Zatloukal, B. Szima, I. Albert, E. Juhász, J.L. Pujol, J. Kozielski, N. Baker, D. Smethurst, W. Stöcklein, W. Piepersberg, A. Surov, P. Clauser, Y.W. Chang, L. Martincich, S.C. Partridge, J.Y. Kim, H.J. Meyer, A. Wienke, A. Suzuki, T. Ito, H. Kawano, M. Hayashida, Y. Hayasaki, Y. Tsutomi, K. Akahane, T. Nakano, M. Miura, K. Shiraki, T. Araki, S. Tahmasebi, T. Alain, V.K. Rajasekhar, J.P. Zhang, M. Prager-Khoutorsky, A. Khoutorsky, Y. Dogan, C.G. Gkogkas, E. Petroulakis, A. Sylvestre, A. Thorburn, K. Behbakht, H. Ford, H. Tian, E.K. Wittmack, T.J. Jorgensen, R. Tohmé, S. Gandhe, G. Tabaro, S. Vallabhaneni, A. Thomas, N. Vasireddi, N.S. Dhawan, A. Ma'ayan, N. Sharma, C. Vaklavas, S.W. Blume, W.E. Grizzle, K. Van der Jeught, H.C. Xu, Y.J. Li, X.B. Lu, G. Ji, A. Montinaro, R.E. Miller, K. Ariail, B. Gliniak, T.S. Griffith, M. Kubin, W. Chin, J. Jones, A. Woodward, T. Le, H. Wang, Y. Liu, J. Ding, Y. Huang, J. Liu, N. Liu, Y. Ao, Y. Hong, L. Wang, L. Zhang, M. Wang, E. Yaaghubi, A.F. Ghilardi, R.B. Ferreira, C.W. Chiang, O.A. Guryanova, D. Kopinke, C.D. Heldermon, S.S. Wang, E.D. Esplin, J.L. Li, L. Huang, A. Gazdar, J. Minna, G.A. Evans, X.W. Wang, Y.J. Zhang, J.S. Warmus, G.J. Dilley, A.I. Meyers, F. Wei, Y. Zhang, L. Geng, P. Zhang, G. Wang, R.H. Weiss, J. Westermarck, N. Wu, Z. Du, Y. Zhu, Y. Song, L. Pang, Z. Chen, J. Xu, P. Wang, H. Yang, J. Zhou, X. Li, W. Xue, C. Yu, Y. Tian, F. Zhu, J.Y. Zhou, W.Z. Wei, G.S. Wu, S.Q. Xu, P. Yaffee, A. Osipov, C. Tan, R. Tuli, A. Hendifar, L. Yong, Z. YuFeng, B. Guang, P.E. Young, C.M. Womeldorph, E.K. Johnson, J.A. Maykel, B. Brucher, A. Stojadinovic, I. Avital, A. Nissan, S.R. Steele, Y. Yu, S.S. Kanwar, B.B. Patel, J. Nautiyal, F.H. Sarkar, A.P. Majumdar, B. Fang, N. Fujita, T. Tsuruo, X. Zhou, W. Liu, X. Hu, A. Dorrance, R. Garzon, P.J. Houghton, C. Shen Show less
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTO Show more
Summary The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents the activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Show less
đź“„ PDF DOI: 10.1016/j.isci.2022.104518
amino-acid synthesis