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Abstract

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  2. Abstract

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF-κB in vitro and has afforded some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that PS-341 induced growth arrest and apoptosis of NCI-H520 and -H460 non-small cell lung cancer (NSCLC) cells in conjunction with markedly up-regulated levels of p21waf1 and p53, and down-regulation of bcl-2 protein in these cells. Also, PS-341 caused phosphorylation of c-Jun NH2-terminal kinase (JNK) and c-Jun, and enhanced AP-1/DNA binding activities in these cells as measured by western blotting and enzyme-linked immunosorbent assay (ELISA), respectively. Interestingly, when the JNK/ c-Jun/AP-1 signal pathway was disrupted by the JNK inhibitor SP600125, the ability of PS-341 to inhibit the growth of NSCLC cells and to up-regulate the levels of p21waf1 in these cells was blunted, but the expression of p53 was sustained at a high level, suggesting that the JNK/c-Jun/AP-1 signal pathway might mediate the anti-lung cancer effects of PS-341, with p21waf1 playing the central role. Thus, PS-341 might be useful for the treatment of individuals with NSCLC.

Abbreviations:
NSCLC

non-small cell lung cancer

MM

multiple myeloma

JNK

c-Jun NH2-terminal kinase

p-JNK

phosphorylate-JNK

ERK

extracellular signal-regulated protein kinase

MAPK

mitogen-activated protein kinase

AP-1

activator protein-1

UPP

ubiquitin-proteasome pathway

NF-κB

nuclear factor-κB

PBS

phosphate-buffered saline

ELISA

enzyme-linked immunosorbent assay

TNFα

tumor necrosis factor α

  • 1
    Adams J. Proteasome inhibitors as new anticancer drugs. Curr Opin Oncol 2002; 14: 62834.
  • 2
    LeBlanc R, Catley LP, Hideshima T, Lentzsch S, Mitsiades CS, Mitsiades N, Neuberg D, Goloubeva O, Pien CS, Adams J, Gupta D, Richardson PG, Munshi NC, Anderson KC. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model. Cancer Res 2002; 62: 49965000.
  • 3
    Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, Adams J, Anderson KC. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002; 277: 1663947.
  • 4
    Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Anderson KC. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001; 61: 30716.
  • 5
    Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 2002; 99: 143749.
  • 6
    Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, Adams J, Esseltine DL, Elliott PJ, Pien CS, Guerciolini R, Anderson JK, Depcik-Smith ND, Bhagat R, Lehman MJ, Novick SC, O'Connor OA, Soignet SL. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002; 20: 44207.
  • 7
    Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, Schlossman R, Podar K, Munshi NC, Mitsiades N, Anderson KC. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 2003; 101: 15304.
  • 8
    Ma MH, Yang HH, Parker K, Manyak S, Friedman JM, Altamirano C, Wu ZQ, Borad MJ, Frantzen M, Roussos E, Neeser J, Mikail A, Adams J, Sjak-Shie N, Vescio RA, Berenson JR. The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemothera-peutic agents. Clin Cancer Res 2003; 9: 113644.
  • 9
    Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemother apeutic agents: therapeutic applications. Blood 2003; 101: 237780.
  • 10
    Richardson PG, Barlogie B, Berenson J, Traynor A, Singhal S, Jagannath S, Irwin D, Rajkumar V, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani S, Esseltine D, Kauffman M, Adams J, Schenkein D, Anderson KC. Phase II study of the proteasome inhibitor PS-341 in multiple myeloma (MM) patients (pts) with relapsed/refractory disease [abstract]. Am Soc Clin Oncol Annu Meet Proc 2002; 11a.
  • 11
    Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 261522.
  • 12
    Ling YH, Liebes L, Jiang JD, Holland JF, Elliott PJ, Adams J, Muggia FM, Perez-Soler R. Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin Cancer Res 2003; 9: 114554.
  • 13
    Adams J. Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer. Curr Opin Chem Biol 2002; 6: 493500.
  • 14
    Karin M. The regulation of AP-1 activity by mitogen-activated protein ki-nases. J Biol Chem 1995; 270: 164836.
  • 15
    Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103: 23952.
  • 16
    Behrens A, Sibilia M, Wagner EF. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 1999; 21: 3269.
  • 17
    Ikezoe T, Chen SS, Tong XJ, Heber D, Taguchi H, Koeffler HP. Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. Int J Oncol 2003; 23: 118793.
  • 18
    Tong X, Xie D, O'Kelly J, Miller CW, Muller-Tidow C, Koeffler HP. Cry61, a member of CCN family, is a tumor suppressor in non-small cell lung cancer. J Biol Chem 2001; 276: 4770914.
  • 19
    Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W, Leisten JC, Motiwala A, Pierce S, Satoh Y, Bhagwat SS, Manning AM, Anderson DW. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 2001; 98: 136816.
  • 20
    Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res 2001; 61: 353540.