Abstract
The molecular basis for the sensitivity of tumor cells to chemopreventive natural food compounds and commonly used chemotherapeutic agents is not well understood, not least because studies are frequently confounded by the diversity among cell lines or rely on experimental protein overexpression. Here we investigated the effects of n-butyrate, a cancer-preventive short-chain fatty acid produced by anaerobic bacteria in the gastrointestinal tract, on the human wild-type p53 and p21 expressing HCT116 colon carcinoma cell line and on HCT116 cells with either p53 or p21 alleles inactivated by homologous recombination. The effects of n-butyrate were then compared with those elicited by cytotoxic drugs and the natural chemopreventive phytoalexin of wine and grapes, resveratrol. We document that physiological concentrations of n-butyrate stimulate p21 expression and induce apoptosis independently of p53, and that the absence of p21 increases apoptosis drastically. The apoptosis is mediated through the mitochondria and is accompanied by mitochondrial proliferation and membrane potential changes. Adriamycin, etoposide, cisplatinum, colcemid and resveratrol induce distinct cellular responses; however, absence of p21 favors apoptosis-induction by adriamycin, etoposide and colcemid. Thus, control of p21 expression may support chemoprevention and certain tumor therapies.
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References
Archer SY, Meng S, Shai A, Hodin R . 1998 Proc. Natl. Acad. Sci. USA 95: 6791–6796
Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, Jacks T . 2000 Genes Dev. 14: 708–718
Atz J, Wagner P, Roemer K . 2000 J. Cell. Biochem. 76: 572–584
Barnard J, Warwick G . 1994 Cell Growth Diff. 4: 495–501
Barshishat M, Polak-Charcon S, Schwartz B . 2000 Br. J. Cancer 82: 195–203
Blandino G, Levine AJ, Oren M . 1999 Oncogene 18: 477–485
Boffa L, Lupton J, Mariani M, Ceppi M, Newmark H, Scalmati A, Lipkin M . 1992 Cancer Res. 52: 5906–5912
Brown JM, Wouters BG . 1999 Cancer Res. 59: 1391–1399
Buckbinder L, Talbott R, Velascomiguel S, Takenaka I, Faha B, Seizinger BR, Kley N . 1995 Nature 377: 646–649
Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, Sedivy JM, Kinzler KW, Vogelstein B . 1998 Science 282: 1497–1501
Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW, Vogelstein B . 1999 J. Clin. Invest. 104: 263–269
Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY . 1995 Science 272: 719–722
Cummings JH . 1981 Gut 22: 763–779
Cupler EJ, Danon MJ, Jay C, Hench K, Popka M, Dalakas MC . 1995 Acta. Neuropathol. 90: 1–6
Fan S, Chang JK, Smith ML, Duba D, Fornace Jr. AJ, O'Connor PM . 1997 Oncogene 14: 2127–2136
Gorospe M, Wang X, Guyton KZ, Holbrook NJ . 1996 Mol. Cell. Biol. 16: 6654–6660
Gorospe M, Cirielli C, Wang X, Seth P, Capogrossi MC, Holbrook NJ . 1997 Oncogene 14: 929–935
Green DR, Reed JC . 1998 Science 281: 1309–1312
Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar AB . 1995 Science 267: 1018–1021
Heerdt B, Houston M, Augenlicht L . 1994 Cancer Res. 54: 3288–3294
Hodin RA, Meng S, Archer S, Tang R . 1996 Cell Growth Diff. 7: 647–653
Hsieh T, Juan G, Darzynkiewicz Z, Wu JM . 1999 Cancer Res. 59: 2596–2601
Huang C, Ma W, Goranson A, Dong Z . 1999 Carcinogenesis 20: 237–242
Huang YQ, Li JJ, Karpatkin S . 2000 J. Biol. Chem. 275: 6462–6468
Hupp TR, Lane DP . 1994 Curr. Biol. 4: 865–875
Jimenez GS, Khan SH, Stommel JM, Wahl GM . 1999 Oncogene 18: 7656–7665
Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, Gudkov AV . 1998 Science 285: 1733–1737
Kroemer G, Reed JC . 2000 Nature Med. 6: 513–519
Li PF, Dietz R, von Harsdorf R . 1999 EMBO J. 18: 6027–6036
Lin Y, Ma W, Benchimol S . 2000 Nature Genet. 26: 122–125
Litvak D, Evers BM, Hwang KO, Hellmich MR, Ko TC, Townsend CM . 1998 Surgery 124: 161–170
Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T . 1994 Science 266: 807–810
Mancini M, Anderson BO, Caldwell E, Sedghinasasb M, Paty PB, Hockenberry DM . 1997 J. Cell Biol. 138: 449–469
Marchenko ND, Zaika A, Moll UM . 2000 J. Biol. Chem. 275: 16202–16212
McBain JA, Eastman A, Nobel S, Mueller GC . 1997 Biochem. Pharmacol. 53: 1357–1368
McIntyre A, Gibson PR, Young GP . 1993 Gut 34: 386–391
Miyashita T, Reed J . 1995 Cell 80: 293–299
Mortensen K, Skouv J, Hougaard DM, Larsson LI . 1999 J. Biol. Chem. 274: 37679–37684
Nakano K, Mizuno T, Sowa Y, Orita T, Yoshino T, Okuyama Y, Fujita T, Ohanti-Fujita N, Matsukawa Y, Tokino T, Yamagishi H, Oka T, Nomura H, Sakai Y . 1997 J. Biol. Chem. 272: 22199–22206
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N . 2000a Science 288: 1053–1058
Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y . 2000b Cell 102: 849–862
Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW, Kruzel E, Radinsky R . 1995 Mol. Cell. Biol. 15: 3032–3040
Polyak K, Waldman T, He T-C, Kinzler KW, Vogelstein B . 1996 Genes Dev. 10: 1945–1952
Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . 1997 Nature 389: 300–305
Reipert S, Berry J, Hughes MF, Hickman JA, Allen TD . 1995 Exp. Cell Res. 221: 281–288
Schwartz B, Besalier RS, Kim YS . 1992 Int. J. Cancer 52: 60–65
Somasundaram K, Zhang H, Zeng Y, Houvras Y, Peng Y, Wu GS, Licht JD, Weber BL, El-Deiry WS . 1997 Nature 389: 187–190
Tian H, Wittmack EK, Jorgensen TJ . 2000 Cancer Res. 60: 679–684
Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB . 1997 Cell 91: 627–637
Waldman T, Kinzler KW, Vogelstein B . 1995 Cancer Res. 55: 5187–5190
Waldman T, Lengauer C, Kinzler KW, Vogelstein B . 1996 Nature 381: 713–716
Waldman T, Zhang Y, Dillehay L, Yu J, Kinzler K, Vogelstein B, Williams J . 1997 Nature Med. 3: 1034–1036
Wang H, Rajagopal S, Reynolds S, Cederberg H, Chakrabarty S . 1999a J. Cell. Physiol. 178: 173–178
Wang Y, Blandino G, Givol D . 1999b Oncogene 18: 2643–2649
Weinstein JN, Myers TG, O'Connor PM, Friend SH, Fornace Jr. AJ, Kohn KW, Fojo T, Bates SE, Rubinstein LV, Anderson NL, Buolamwini JK, von Osdol WW, Monks AP, Scudiero DA, Sausville EA, Zaharevitz DW, Bunow B, Viswanadhan VN, Johnson GS, Wittes RE, Paull KD . 1997 Science 275: 343–349
Wu GS, Burns TF, McDonald ER III, Jiang W, Meng R, Krantz ID, Kao G, Gan D-D, Zhou J-Y, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, El-Deiry WS . 1997 Nature Genet. 17: 141–143
Yin Y, Terauchi Y, Solomon GG, Aizawa S, Ranagarajan PN, Yazaki Y, Kadowaki T, Barrett JC . 1998 Nature 391: 707–710
Acknowledgements
We are grateful to Bert Vogelstein for the HCT116 cell lines. This work was in part supported by grant SFB399 (B5) from the German Research Foundation (DFG).
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Mahyar-Roemer, M., Roemer, K. p21 Waf1/Cip1 can protect human colon carcinoma cells against p53-dependent and p53-independent apoptosis induced by natural chemopreventive and therapeutic agents. Oncogene 20, 3387–3398 (2001). https://doi.org/10.1038/sj.onc.1204440
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DOI: https://doi.org/10.1038/sj.onc.1204440
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