Regulation of p38 phosphorylation and topoisomerase IIalpha expression in the B-cell lymphoma line Jiyoye by CD26/dipeptidyl peptidase IV is associated with enhanced in vitro and in vivo sensitivity to doxorubicin.
CD26 is a Mr 110,000 surface-bound glycoprotein with diverse functional properties, including having a key role in normal T-cell physiology and the development of certain cancers. In this article, we show that surface expression of CD26, especially its intrinsic dipeptidyl peptidase IV (DPPIV) enzyme activity, results in enhanced topoisomerase IIalpha level in the B-cell line Jiyoye and subsequent in vitro sensitivity to doxorubicin-induced apoptosis. In addition, we show that expression of CD26/DPPIV is associated with increased phosphorylation of p38 and its upstream regulators mitogen-activated protein kinase kinase 3/6 and apoptosis signal-regulating kinase 1 and that p38 signaling pathway plays a role in the regulation of topoisomerase IIalpha expression. Besides demonstrating that CD26 effect on topoisomerase IIalpha and doxorubicin sensitivity is applicable to cell lines of both B-cell and T-cell lineages, the potential clinical implication of our work lies with the fact that we now show for the first time that our in vitro results can be extended to a severe combined immunodeficient mouse model. Our findings that CD26 expression can be an in vivo marker of tumor sensitivity to doxorubicin treatment may lead to future treatment strategies targeting CD26/DPPIV for selected human cancers in the clinical setting. Our article thus characterizes the biochemical linkage among CD26, p38, and topoisomerase IIalpha while providing evidence that CD26-associated topoisomerase IIalpha expression results in greater in vitro and in vivo tumor sensitivity to the antineoplastic agent doxorubicin.
Yamochi
Toshiko
T
Department of Lymphoma/Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Yamochi
Tadanori
T
Aytac
Ugur
U
Sato
Tsutomu
T
Sato
Kazuya
K
Ohnuma
Kei
K
McKee
Kathryn S
KS
Morimoto
Chikao
C
Dang
Nam H
NH
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000378:metabolism; D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000378:metabolism; D015996:Survival Rate; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017304:Annexin A5; D000903:Antibiotics, Antineoplastic; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D018819:Dipeptidyl Peptidase 4; D004250:DNA Topoisomerases, Type II