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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1724-1731
By
From the Department of Genetics and Pathology and Department of
Medical Sciences, University Hospital, Uppsala, Sweden.
Somatostatin and its analogs can inhibit growth in several cell
types, in part by interfering with insulin-like growth factor-I (IGF-I)
signaling. Our previous studies point to the importance of paracrine
and autocrine IGF-I in the support of growth and survival of human
multiple myeloma (MM) cell lines. In this report, we have investigated
the potential role of a somatostatin analog, octreotide, in regulating
growth and/or survival in MM. The results show that all MM cell
lines express functional somatostatin receptors (sst). The MM cell
lines express the subtypes sst2, sst3, and predominantly sst5 as determined by reverse-transcriptase
polymerase chain reaction and fluorescence-activated cell sorter
analysis. Octreotide inhibited the growth of both the interleukin-6
(IL-6)-dependent and the IL-6-independent MM cell lines. The effect
is mainly cytostatic, resulting in 25% to 45% growth inhibition, and
in three of eight of the MM cell lines a weak induction of apoptosis
was recorded. Our results also show that octreotide may act as an
inducer of apoptosis in primary B-B4+ plasma cells
isolated from bone marrow of MM patients. In conclusion, the results
show a novel pathway for growth inhibition of MM cells: the activation
of somatostatin receptor signaling.
HUMAN MULTIPLE MYELOMA (MM) is a clonal
expansion of malignant plasmablasts-plasma cells in the bone marrow.
The growth of MM cells is regulated by complex interactions between the
malignant cells and cells of the microenvironment, eg, osteoblasts and
stroma cells.1 Interleukin-6 (IL-6) is a major growth
factor both in vitro and in vivo, but several other cytokines have been
reported to stimulate the growth of MM cell lines and/or
freshly explanted MM cells.2 We and others have recently
shown that insulin-like growth factor-I (IGF-I) can promote growth
and/or survival of MM cell lines.3,4 We also showed
that IGF-I is produced by MM cell lines, and that an autocrine IGF-I
loop may participate in maintaining growth and survival in MM cell
lines.3
So far only a few factors have been shown to inhibit the growth of MM
cells. Interferon (IFN)- Analogous to the inhibitory effect of IFNs on IL-6 signaling,
somatostatin and its analogs can inhibit growth by interfering with
IGF-I signaling in normal and malignant cells.11
Downregulation of IGF-I,12 upregulation of the expression
of inhibitory IGF-I-binding proteins,13 and inhibition of
the mitogenic signaling via the IGF-I receptor
(IGF-IR)14,15 have been reported as plausible mechanisms
mediating the growth-inhibitory effect of the somatostatin analog octreotide.
Somatostatin acts as a neurotransmitter and a general inhibitor of
secretion, and can induce antiproliferative effects in, for example,
activated peripheral blood lymphocytes (PBL) and intestinal mucosa
lymphocytes.16 The growth-inhibitory effect has been
suggested to be subtype-specific, since cells with high-affinity receptors are more sensitive to somatostatin-induced growth
inhibition.16,17 The knowledge of somatostatin receptor
(sst) expression in lymphocytes is incomplete. In receptor-binding
assays, normal resting PBL express low-affinity sst, while activated
PBL, lymphoblastic leukemia cells, and Epstein-Barr virus
(EBV)-positive B cells usually express high-affinity
sst.17 The U-266 MM cell line has been shown to express
both low-and high-affinity sst.18 Five different sst subtypes have now been cloned,19-21 and a growth-inhibitory
signal has been shown to be mediated by sst1,
sst2, and sst5 through different
mechanisms.22,23 Furthermore, sst3 activation
may induce apoptosis.24 The function of sst4,
which has a low affinity for somatostatin compared with the other sst
subtypes, is essentially unknown. The knowledge of subtype expression
in hematopoietic cells is limited, but sst2,
sst3, and sst5 have been found in some B- and
T-cell lines.25
Based on our earlier results, showing IGF-I stimulation of growth
and/or survival of MM cell lines and the ability of octreotide to inhibit IGF-I signaling in several cell types, we examined the
expression of sst subtypes in MM cells and whether such receptors, when
expressed, may transmit growth-inhibitory signals following binding of
the somatostatin analog octreotide. The response of primary isolated
B-B4+ cells to octreotide was also examined. By
reverse-transcriptase polymerase chain reaction (RT-PCR) and flow
cytometry, all MM cell lines in the panel were found to express
sst2, sst3, and sst5 both at the
RNA level and on the cell surface. Octreotide inhibited the growth of
both IL-6-independent and IL-6-dependent cell lines and a weak
induction of apoptosis in three of eight MM cell lines was recorded.
Our results also indicate that octreotide may induce apoptosis in
freshly explanted MM cells.
Cell lines.
A panel of eight human MM cell lines, previously examined for their
response to IGF-I and IL-6, was selected (Table
1). The panel included two cell lines
(U-266 and HL407) in which a progression from IL-6 dependence at early
passages (U-266-197026 and HL 407E27) to IL-6
independence has occurred during long-term in vitro culture
(U-266-198428 and H407L27). The
IL-6-independent cell lines (LP-1,29 EJM,30
Karpas 707,31 HL407L, and U-266-1984) are maintained in
RPMI 1640 (Flow, Irvine, UK) supplemented with 10% fetal bovine serum
(FBS; GIBCO, Grand Island, NY), glutamine, and antibiotics (penicillin
100 U/mL and streptomycin 50 µg/mL). The IL-6-dependent cell lines
(U-1958,32 HL407E, and U-266-1970) are grown on human
fibroblasts, AG 1523, purchased from the Human Mutant Genetic Cell
Repository (Camden, NJ) and maintained in the same medium as the
IL-6-independent cell lines. Medium is replenished twice a week.
Receptor-binding studies.
The cells were incubated in acidic medium (RPMI 1640, pH 3) for 1 minute to remove bound ligand, washed, and then kept in binding buffer
(phosphate-buffered saline [PBS], 1% FBS, HEPES 10 mmol/L pH 7.2, aprotinin 2.8 µg/mL, phenylmethylsulfonyl fluoride [PMSF] 0.2 mmol/L). A 10,000 cpm quantity of 125I-somatostatin (2,000 Ci/mmol; Amersham, Essex, UK) was added to each well
containing 106 cells. Cold somatostatin
(10 PCR.
Exponentially growing cells from stock cultures were harvested, and RNA
was extracted using a modified version of the single-step method
established by Chomczynski and Sacchi.33 cDNA was
synthesized from 1 µg of RNA and primed with oligo-d(T) as described
elsewhere.34 For each PCR, we used 1/10 of a cDNA synthesis
reaction. Amplification was performed for 35 cycles. The annealing
temperature was 60°C for all reactions. The ubiquitously expressed
G3PDH gene was used as a control for the quality of the cDNA. Primers
were purchased from Scandinavian Gene Synthesis (Köping, Sweden).
The primer sequences used are as previously described35,36:
sst2 primers Development of rabbit antihuman sst antibodies.
Deduced from the amino acid sequences of human sst subtypes
sst2, sst3, and sst5,21
three polypeptides were synthesized by a solid-phase system using Fmoc
chemistry (Applied Biosystems Model 430A). The peptides were purified
by reverse-phase chromatography and analyzed by plasma desorption mass
spectrometry (PDMS; Bioion 20, Bioion Nordic AB, Uppsala, Sweden). The
sequences were selected to be specific for the different sst subtypes
and the homology was less than 48% to any other known protein sequence
in the data bank MPsrch Protein, version 1.5 (Shane S. Surrock & John
F. Collins 1993, Biocomputing Research Unit, University of Edinburgh,
UK), except for the respective sequences of sst from other species. The
sequences were amino acids 330 to 343 for sst2, amino acids 366 to 381 for sst3, and amino acids 327 to 341 for
sst5, all with additional tyrosine residues at the
N-terminals (Tyr0) and amidated C-terminals. Before immunization, the
peptides were coupled to a carrier protein. Peptide (2 mg) and 20 mg
bovine serum albumin were dissolved in a 50 mmol/L sodium phosphate
buffer at pH 7.4, containing 150 mmol/L NaCl. Coupling was then induced
by addition of 90 µL glutaraldehyde.37 The resulting
complexes were injected into white New Zealand rabbits, using the
intradermal injection technique, to produce polyclonal
antibodies.38
Flow cytometry.
Exponentially growing cells were pretreated with acidic medium as
described earlier and then kept in PBS with 1% FBS. The rabbit
antihuman sst antisera were diluted 1:6 and incubated with the cells
for 30 minutes on ice. Normal rabbit serum from the same rabbits was
used as a negative control. The cells were then washed three times and
incubated for 30 minutes on ice with fluorescein-conjugated swine
antirabbit antibodies (1:30) (Dako A/S, Glostrup, Denmark) and analyzed
in a flow cytometer (FACScan; Becton Dickinson, San José, CA). To
allow comparison between cell lines with different levels of
autofluorescence, the mean fluorescence (MFI) was expressed as relative
fluorescence, where the negative control was arbitrarily set to 1. The
results are presented as the MFI from three experiments ± SEM.
Growth and survival assays.
Exponentially growing cells were seeded at a concentration of 4 × 10 5 cells/mL in RPMI 1640 with 10% FBS, glutamine, and
antibiotics. IL-6 (50 U/mL; R&D Systems, Abington, UK) was added to
cultures of IL-6-dependent cells. Octreotide (Novartis Pharma AG,
Basel, Switzerland) was added at concentrations ranging from 0 to 1,000 nmol/L. In a few experiments, native somatostatin (Sigma) was used in
parallel at the same concentrations and was added every 12 hours.
Octreotide binds to sst2, sst3, and
sst5, while somatostatin binds to all sst
subtypes.22 The cells were then incubated at +37°C for 48 hours, harvested, and total and viable
cell numbers determined using a Bürker chamber and Trypan blue
exclusion. In some experiments, the apoptotic cells were analyzed using
annexin V/propidium iodide (PI) staining (R&D Systems) according to the
manufacturer's instructions. The number of apoptotic cells was
determined as the percentage of annexin V-positive, PI-negative cells.
The B-B4+ primary cells were seeded at 6 × 10 5 cells/mL in RPMI 1640, 10% FBS, glutamine, and
antibiotics. Octreotide (10 Cell cycle analysis.
We also performed PI staining of cell nuclei to analyze the cell cycle
distribution as described elsewhere.39 Briefly, cells were
incubated without or with 10 sst binding.
To investigate the expression of ssts on the panel of MM cell lines, we
performed receptor binding studies using 125I-somatostatin.
The MM cells were pretreated with acidic medium to remove bound ligand.
The cells were then incubated with 125I-somatostatin in the
absence or presence of a large excess of cold somatostatin
(10
sst subtype expression.
To investigate sst subtype expression on the different MM cell lines,
we isolated RNA from exponentially growing cells from each cell line,
synthesized cDNA, and performed PCR for sst2, sst3, and sst5. As shown in Fig
2, all cell lines expressed mRNA for all
three sst subtypes investigated. The PCR reached the plateau phase
before 35 cycles in some reactions; therefore, quantification of
different expression levels is not possible in this experimental set-up. The human sst genes, except sst2, lack introns and
contamination by genomic DNA would yield products of the same size.
Therefore, we included tubes without RT in the cDNA synthesis
reactions. Amplification of these templates were all negative (data not
shown). The specificity of the PCR products was confirmed by size and restriction fragment analysis using Bal I, Sac I, and
Hga I for sst2, sst3, and
sst5, respectively, and G3PDH was used as a control for the
quality of the cDNA. Furthermore, the specificity of the products was
also confirmed by sequencing as described in Materials and Methods
(data not shown).
Effect of octreotide on growth of MM cells.
Exponentially growing cells from the MM cell lines were harvested,
washed twice, and then seeded at 4 × 10 5 cells/mL in
48-well plates. The cells were incubated in RPMI 1640 with 10% FBS,
glutamine, antibiotics, and different concentrations of octreotide (0 to 1,000 nmol/L). After 48 hours, the cells were harvested and total
and viable cells were counted using Trypan blue exclusion. To simplify
comparisons between the MM cell lines, which have a wide range of
population doubling times, the number of viable cells was plotted as
the percentage of exponentially growing control cells. As depicted in
Fig 4, cells from all MM cell lines were
growth-inhibited in a dose-dependent manner by octreotide. The growth
was inhibited by 25% to 45%. When octreotide was substituted by
somatostatin, the inhibitory effect on growth was essentially the same
(data not shown). No systematic difference between IL-6-independent
(Fig 4A) and IL-6-dependent cell lines (Fig 4B) could be recorded. The
strongest growth inhibition (40% to 45%) was seen in cells from the
LP-1 and HL407L cell lines. The weakest response (25%) was seen in
cells of the U-266 cell lines (U-266-1970 and U-266-1984). In a
majority of the cell lines, the growth inhibition was not accompanied
by a decrease in viability, the exception being the U-1958, HL407E, and
HL407L cell lines, where a minor decrease in the viability was recorded
(Table 2). Annexin V/PI staining of cells
from the U-1958, HL407E, and HL407L cell lines showed a small increase
in the number of apoptotic cells in cell cultures treated with
octreotide (Table 2).
Somatostatin and its analogs inhibit growth of several types of tumor
cells in vitro, eg, breast and prostate cancer cells.40,41 Several mechanisms have been suggested by which somatostatin and octreotide might inhibit the growth of tumor cells. One pathway is by
interfering with IGF-IR signaling.
Submitted May 4, 1998; accepted September 26, 1998.
Supported by grants from the Swedish Cancer Society.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Kenneth Nilsson, MD, PhD, Laboratory of
Tumor Biology, Department of Genetics and Pathology, University
Hospital, S-751 85 Uppsala, Sweden.
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