The effects on growth and survival of IL‐6 can be dissociated in the U‐266‐1970/U‐266‐1984 and HL407E/HL407L human multiple myeloma cell lines

Spets, Helena; Jernberg-Wiklund, Helena; Sambade, Clara; Söderberg, Ola; Nilsson, Kenneth

doi:10.1046/j.1365-2141.1997.1903004.x

Cited by 16 publications

(17 citation statements)

References 21 publications

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“…Both of these defects can result from the action of IL-6. Multiple previous studies have demonstrated that IL-6 can cause plasma cell proliferation (Jelinek et al, 1997;Klein et al, 1995;Lichtenstein et al, 1989;Ogata et al, 1997;Spets et al, 1997;Urashima et al, 1997;Westendorf et al, 1994Westendorf et al, , 1996. It has also been demonstrated that IL-6 and IGFs can protect myeloma cells from dexamethasone-induced apoptosis (Lichtenstein et al, 1995;Xu et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders

Witzig¹,

Timm²,

Larson

et al. 1999

Br J Haematol

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Summary. The proliferative rate of malignant plasma cells, as measured by the plasma cell labelling index (PCLI), is an important prognostic factor in multiple myeloma (MM); however, the PCLI alone is probably inadequate to describe tumour growth because it ignores the idea that myeloma cells may have a reduced rate of apoptosis. The aims of this study were to develop a flow cytometric method to measure the apoptosis index of fresh marrow plasma cells and develop a plasma cell growth index (PCGI) that related both proliferation and apoptosis to disease activity. Marrow aspirates were obtained from 91 patients with plasma cell disorders and the plasma cells in apoptosis were identified by either 7-amino actinomycin-D (7-AAD) or annexin V-FITC three-colour flow cytometry. The median plasma cell apoptotic index (PCAI) for patients with monoclonal gammopathy of undetermined significance (MGUS), smouldering or indolent myeloma (SMM/IMM), and new multiple myeloma (MM) was 5·2, 3·4 and 2·4, respectively (P¼0·03, MGUS v MM). The median PCLI for these same patient groups was 0·0, 0·2 and 0·6, respectively (P<0·001, MGUS v MM). The paired PCLI and PCAI for each sample were used to derive the PCGI ¼ 2 þ [PCLI ¹ (0·1)(PCAI)]. The median PCGI for patients with inactive disease (MGUS, SMM/IMM or amyloidosis) was 1·8 compared to 2·4 for those with active disease (new or relapsed MM) (P < 0·001). These results suggest that a decrease in the PCAI may be a factor in the progression from MGUS to SMM to overt MM.

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Section: Discussionmentioning

confidence: 98%

Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders

Witzig¹,

Timm²,

Larson

et al. 1999

Br J Haematol

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“…24 The MCCs included at least 98% plasma cells and were used at early passages; thus, they had biologic characteristics resembling those of freshly expanded myeloma cells. The 2 myeloma cell lines, IM-9 and U-266-1970 (early passage), 27,38 were used as controls for IL-6-independent and IL-6-dependent myeloma cell lines, respectively. 8…”

Section: Bmmc and Cell Culturesmentioning

confidence: 99%

“…Experimental evidence suggests that these 2 effects are dissociable and mediated by distinct signaling pathways. 27 Interaction of IL-6 with its ␣-chain receptor, gp80, induces homodimerization of gp130, the signal-transducing receptor component, as well as activation of different downstream pathways, such as activation of Stat-1, Stat-3, or Ras proteins, with subsequent activation of the kinase cascade that includes the mitogen-activated protein kinases (MAPK). [28][29] Activation of the MAPK cascade induces cell growth, whereas the Stat-3 pathway has an antiapoptotic effect.…”

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confidence: 99%

Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis

Frassanito

Cusmai

Iodice

et al. 2001

Blood

143

112

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In this study, flow cytometry was used to evaluate interleukin-6 (IL-6) production by bone marrow mononuclear cells from 47 patients with multiple myeloma (MM) in different clinical stages and 15 patients with monoclonal gammopathy of undetermined significance. In patients with MM, autocrine IL-6 production paralleled the clinical disease stage. The largest proportion of syndecan-1 ؉ /IL-6 ؉ cells was detected in patients with resistant relapse or primary refractory disease, suggesting that tumor progression involves expansion of myeloma cells producing IL-6. The authors assessed autocrine IL-6 production and in vitro proliferation and apoptosis of myeloma cells in 6 myeloma cell clones (MCCs) and in 2 myeloma cell lines, namely IM-9 and U-266-1970, which showed different sensitivities to the addition of exogenous IL-6. Autocrine IL-6 production was observed in IL-6-independent MCC-2, MCC-3, and MCC-5 cloned from patients with aggressive disease and in the IM-9 cell line. In contrast, IL-6-dependent MCC-1, MCC-4, and MCC-6 were syndecan-1 ؉ and IL-6 ؊ . Blocking experiments with anti-IL-6 monoclonal antibody from clone AH65, which binds IL-6-IL-6R␣ complexes, prevented cell proliferation of IL-6 ؉ MCCs. Flow cytometry evaluations after propidium iodide staining revealed different susceptibilities of MCCs to cell death. IL-6-producing MCCs showed minimal spontaneous and dexamethasone-induced apoptosis, whereas a regular amplitude of apoptosis occurred in the IL-6 ؊ MCCs. These data provide evidence that autocrine IL-6 reflects a highly malignant phenotype of myeloma cells. In fact, autocrine IL-6 production and deregulated apoptosis may induce expansion of selective IL-6 ؉ myeloma cells resistant to spontaneous and drug-induced cell death. IntroductionInterleukin 6 (IL-6), a pleiotropic cytokine produced by a variety of cells, is the most important growth factor for human multiple myeloma (MM). 1-3 Several findings support in vivo and in vitro roles for IL-6 in the disease: specifically, (1) serum IL-6 and IL-6R levels were found to correlate with disease activity 4-6 ; (2) therapy with anti-IL-6 monoclonal antibody (mAb) transiently reversed disease manifestations 7 ; (3) in vitro proliferation of myeloma cells was suppressed by neutralizing mAbs to either IL-6 or its cellular receptors [8][9] ; and (4) inactivation of IL-6 messenger RNA by antisense oligonucleotides inhibited proliferation of plasma cells. 10 Furthermore, other cytokines, such as IL-1, IL-3, and granulocytemacrophage colony-stimulating factor, regulate myeloma cell proliferation in synergy with IL-6 11 or by inducing IL-6 production in myeloma cells or the tumor environment. [12][13] The cellular origin of IL-6 is controversial. Several authors [13][14][15][16] showed that it is produced by the myeloma cells themselves (autocrine hypothesis). Other studies, [17][18][19] however, point to its paracrine production by cells in the bone marrow (BM) and suggest that proliferation of myeloma cells depends on close contact with stromal cells. [20][21...

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“…Experimental evidence suggests that these two effects are dissociable and mediated by distinct signalling pathways (Fukada et al , 1996; Ogata et al , 1997; Spets et al , 1997). Stat‐3 activation has an anti‐apoptotic effect (Fukada et al , 1996; Spets et al , 1997), and activation of Ras protein induces cell growth (Ogata et al , 1997). Furthermore, transfection of activated Ras‐complementary DNA into the IL‐6‐dependent ANBL6 myeloma cell line induced IL‐6‐independent cell growth and resistance to drug‐induced apoptosis (Billadeau et al , 1997), suggesting that Ras mutations may be related to autocrine IL‐6 production (Lubbert et al , 1993), myeloma cell growth and response to therapy (Billadeau et al , 1997).…”

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confidence: 99%

Manumycin inhibits farnesyltransferase and induces apoptosis of drug‐resistant interleukin 6‐producing myeloma cells

et al. 2002

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Summary. Interleukin 6 (IL-6) is an important survival and growth factor for myeloma cells and exerts its effects by activating several transduction pathways, including the Ras cascade. As farnesylation of the activated Ras oncogene product by protein farnesyltransferase (FTase) is a critical step for Ras functional activity, FTase has emerged as a potential target for the development of new anti-cancer agents. Based on our previous demonstration that IL-6-producing myeloma cells are refractory to drug-induced apoptosis, we have analysed the effect of manumycin, a natural FTase inhibitor, on IL-6-producing myeloma cells resistant to Fas-, dexamethasone-and doxorubicin-induced apoptosis. Treatment of myeloma cells with manumycin prevented cell proliferation and induced apoptosis. Western blotting experiments demonstrated that this effect was related to inhibition of the post-translational Ras processing. Further analysis showed that manumycin-induced apoptosis involved caspase-3. Activation of caspase-3, in fact, was observed in 6 h-treated myeloma cells expressing Apo 2AE7 antigen, the marker of early apoptosis, whereas their treatment with cell-permeable DEVD-fmk, that irreversibly inhibits caspase-3 activity, prevented their apoptosis. Overexpression of caspase-3 was also demonstrated by reverse transcription-polymerase chain reaction. Finally, overexpression of Bcl-2 and its homologue Bcl-xL was observed in manumycin-treated cells as well as in control myeloma cells, implying that the Bcl-2 family is not involved. FTase inhibitors may thus be proposed as a potential pharmacological weapon, as they block the Ras pathway and induce the apoptosis of drug-resistant IL-6-producing myeloma cells.

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The effects on growth and survival of IL‐6 can be dissociated in the U‐266‐1970/U‐266‐1984 and HL407E/HL407L human multiple myeloma cell lines

Cited by 16 publications

References 21 publications

Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders

Measurement of apoptosis and proliferation of bone marrow plasma cells in patients with plasma cell proliferative disorders

Autocrine interleukin-6 production and highly malignant multiple myeloma: relation with resistance to drug-induced apoptosis

Manumycin inhibits farnesyltransferase and induces apoptosis of drug‐resistant interleukin 6‐producing myeloma cells

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