Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling

다국어 초록 (Multilingual Abstract)

Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation.
Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E,the sole Drosophila STAT homolog. Consequently,BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin’s lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin’s lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression.
These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling,specifically Hodgkin’s lymphoma.

참고문헌 (Reference)

1 Müller M, "The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction" 366 : 129-135, 1993

2 Chung EY, "The benzoxathiolone LYR-71 down-regulates interferon-gamma-inducible pro-inflammatory genes by uncoupling tyrosine phosphorylation of STAT-1 in macrophages" NATURE PUBLISHING GROUP 158 : 1971-1981, 2009

3 Hou XS, "The JAK-STAT pathway in Drosophila" 13 : 105-110, 1997

4 Meraz MA, "Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway" 84 : 431-442, 1996

5 Miyoshi K, "Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor" 131 : 108-117, 2011

6 Flex E, "Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia" 205 : 751-758, 2008

7 Klampfer L, "Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs" 6 : 107-121, 2006

8 Yu H, "STATs in cancer inflammation and immunity: a leading role for STAT3" 9 : 798-809, 2009

9 Darnell JE Jr, "STATs and gene regulation" 277 : 1630-1635, 1997

10 Hazan-Halevy I, "STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells" 115 : 2852-2863, 2010

11 Al Zaid Siddiquee K, "STAT3 as a target for inducing apoptosis in solid and hematological tumors" 18 : 254-267, 2008

12 Takeda K, "STAT family of transcription factors in cytokine-mediated biological responses" 11 : 199-207, 2000

13 Niu G, "Roles of activated Src and Stat3 signaling in melanoma tumor cell growth" 21 : 7001-7010, 2002

14 Atallah E, "Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms" 9 : 663-670, 2009

15 Herrmann A, "Nucleocytoplasmic shuttling of persistently activated STAT3" 120 : 3249-3261, 2007

16 Oh ST, "Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms" 116 : 988-992, 2010

17 Kim MH, "Novel iminobenzoxathiolone compound inhibits nuclear factor-kappaB activation targeting inhibitory kappaB kinase beta and down-regulating interleukin-1beta expression in lipopolysaccharide- activated macrophages" 76 : 373-381, 2008

18 Kim BH, "NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3" 9 : 36-, 2010

19 Bercovich D, "Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome" 372 : 1484-1492, 2008

20 Fletcher S, "Molecular disruption of oncogenic signal transducer and activator of transcription 3 (STAT3) protein" 87 : 825-833, 2009

21 Kim BH, "MS-1020 is a novel small molecule that selectively inhibits JAK3 activity" BLACKWELL PUBLISHING 148 : 132-143, 2010

22 Lius V, "Local treatment of acne with tioxolone" 76 : 39-41, 1979

23 Ja Eun Kim, "LYR71, a derivative of trimeric resveratrol, inhibits tumorigenesis by blocking STAT3-mediated matrix metalloproteinase 9 expression" 생화학분생물학회 40 (40): 514-522, 2008

24 Neubauer H, "Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis" 93 : 397-409, 1998

25 Chang BY, "JAK3 inhibition significantly attenuates psoriasiform skin inflammation in CD18 mutant PL/J mice" 183 : 2183-2192, 2009

26 Steelman LS, "JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis" 18 : 189-218, 2004

27 Arbouzova NI, "JAK/STAT signalling in Drosophila: insights into conserved regulatory and cellular functions" 133 : 2605-2616, 2006

28 Mullighan CG, "JAK mutations in high-risk childhood acute lymphoblastic leukemia" 106 : 9414-9418, 2009

29 Schindler C, "Interferondependent tyrosine phosphorylation of a latent cytoplasmic transcription factor" 257 : 809-813, 1992

30 Schindler C, "Inteferons pen the JAK-STAT pathway" 19 : 311-318, 2008

31 Decker P, "Inhibition of caspase-3- mediated poly(ADP-ribose) polymerase (PARP) apoptotic cleavage by human PARP autoantibodies and effect on cells undergoing apoptosis" 275 : 9043-9046, 2000

32 Haftchenary S, "Inhibiting aberrant Stat3 function with molecular therapeutics: a progress report" 22 : 115-127, 2011

33 Park SY, "Developmental defects of lymphoid cells in Jak3 kinase-deficient mice" 3 : 771-782, 1995

34 Garcia R, "Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells" 20 : 2499-2513, 2001

35 Watling D, "Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway" 366 : 166-170, 1993

36 Kim BH, "Benzoxathiole derivative blocks lipopolysaccharideinduced nuclear factor-kappaB activation and nuclear factorkappaB- regulated gene transcription through inactivating inhibitory kappaB kinase beta" 73 : 1309-1318, 2008

37 Goeth H, "Antimicrobial and cytostatic properties of 6-hydroxy-1,3-benzoxathiol-2-one (01 1)" 19 : 1298-1304, 1969

38 Shuai K, "Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein" 258 : 1808-1812, 1992

39 Walters DK, "Activating alleles of JAK3 in acute megakaryoblastic leukemia" 10 : 65-75, 2006

40 James C, "A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera" 434 : 1144-1148, 2005

41 Kim BH, "A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells" AMER ASSOC CANCER RESEARCH 7 (7): 2672-2680, 2008

42 Bach EA, "A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway" 165 : 1149-1166, 2003

43 Iwamaru A, "A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo" 26 : 2435-2444, 2007

44 O'Shea JJ, "A new modality for immunosuppression: targeting the JAK/STAT pathway" 3 : 555-564, 2004

45 Wildfeuer A, "6-hydroxy-1,3-benzoxathiol-2-one, an antipsoriatic with antibacterial and antimycotic properties" 20 : 824-831, 1970