Page 376 - 2014 Printable Abstract Book
P. 376
(PS7-40) Pasireotide activates signal transduction pathway of KLF-4 and Oct-4 expression via
somatostatin receptors 3 and 5. Qiang Fu; Daohong Zhou; and Martin Hauer-Jensen, UAMS, Little Rock,
AR
Background: Somatostatin, a regulatory peptide produced by endocrine and non-endocrine
tissues in response to different stimuli, inhibits various cellular functions including secretion, motility and
proliferation. These actions of somatostatin are mediated by five specific somatostatin receptors (SST1-
SST5) which are differentially regulated and expressed in various tissues. The five somatostatin receptor
subtypes share common signaling pathways. Pasireotide (SOM230) is a second generation somatostatin
analog that binds with high affinity to human SST1, 2, 3, and 5. Earlier studies performed in our
laboratories showed that pasireotide exerts potent radioprophylactic and radiation mitigating effects
after total body irradiation (TBI) by reducing radiation-induced inflammatory cytokines and inhibiting
exocrine pancreatic secretion. To unravel the molecular mechanism underlying the radioprotective
properties of pasireotide, we assessed the signal transduction pathway activation in a cell line with stably
expressed human somatostatin receptor subtypes. Methods: HEK293 cells, a cell line that does not
normally express somatostatin receptors, were stably transfected with individual human somatostatin
receptor subtypes and then transiently transfected with transcription factor reporter vector. The activities
of five different stem cell transcription factors were estimated by normalized luciferase activities of the
reporter after pasireotide treatment. Results: Pasireotide activated the signal transduction pathways of
stem cell transcription factors KLF-4 and Oct-4 via SST3 and SST5, but not via somatostatin receptors 1, 2
and 4. Conclusion: KLF-4 is highly expressed in the gastrointestinal tract where it is involved in enterocyte
differentiation. Oct-4, although first known as a transcription factor in embryonic stem cells, also plays a
role in sustaining self-renewal capacity of adult somatic stem cells and in regulating DNA repair genes.
Our finding that pasireotide activates the signal transduction pathways of both transcription factors via
SST3 and SST5 suggests that the mechanism of radioprotection not only involves amelioration of
gastrointestinal injury, but also the promotion of stem cell self-renewal, stem cell differentiation, and DNA
repair.
1;1
(PS7-41) Cyclin B1/CDK1 enhances mitochondrial bioenergetics in radiation response. Lili Qin, PhD MD
1;2
1
and Jian Jian Li, PhD MD ; University of California, Davis, Sacramento, CA and university of California,
Davis, Sacramento, CA
2
Mammalian cells can induce an adaptive response under a certain level of genotoxic stresses
including low dose ionizing radiation. The mechanisms underlying such adaptive radioprotection,
especially mitochondria-associated homeostasis, are poorly understood. In this study, we found that
human mammary epithelial cells (MCF-10A) exhibit enhanced mitochondria ATP production and oxygen
consumption with a peak at 24h after exposure to 5 Gy radiation along with increased level of
mitochondria superoxide. Similar alterations of mitochondria metabolism were found in human skin
keratinocytes (HK18) and mouse skin epithelia cells (JB6) with different peak times of mitochondrial
respiration. In addition, G2/M regulator Cyclin B1/CDK1 was found translocated to mitochondria of MCF-
10A cells after radiation as well as post-G2/M transition. The mitochondrial relocation of CyclinB1/CDK1
was linked with DNA repair and mitochondrial activation and dominant negative CDK1 targeted to
mitochondria reverses enhanced mitochondrial ATP production caused by mitochondria targeting wild-
type CDK1. Dramatically, cellular DNA damage repair capacity detected by H2AX foci formation was
374 | P a g e
somatostatin receptors 3 and 5. Qiang Fu; Daohong Zhou; and Martin Hauer-Jensen, UAMS, Little Rock,
AR
Background: Somatostatin, a regulatory peptide produced by endocrine and non-endocrine
tissues in response to different stimuli, inhibits various cellular functions including secretion, motility and
proliferation. These actions of somatostatin are mediated by five specific somatostatin receptors (SST1-
SST5) which are differentially regulated and expressed in various tissues. The five somatostatin receptor
subtypes share common signaling pathways. Pasireotide (SOM230) is a second generation somatostatin
analog that binds with high affinity to human SST1, 2, 3, and 5. Earlier studies performed in our
laboratories showed that pasireotide exerts potent radioprophylactic and radiation mitigating effects
after total body irradiation (TBI) by reducing radiation-induced inflammatory cytokines and inhibiting
exocrine pancreatic secretion. To unravel the molecular mechanism underlying the radioprotective
properties of pasireotide, we assessed the signal transduction pathway activation in a cell line with stably
expressed human somatostatin receptor subtypes. Methods: HEK293 cells, a cell line that does not
normally express somatostatin receptors, were stably transfected with individual human somatostatin
receptor subtypes and then transiently transfected with transcription factor reporter vector. The activities
of five different stem cell transcription factors were estimated by normalized luciferase activities of the
reporter after pasireotide treatment. Results: Pasireotide activated the signal transduction pathways of
stem cell transcription factors KLF-4 and Oct-4 via SST3 and SST5, but not via somatostatin receptors 1, 2
and 4. Conclusion: KLF-4 is highly expressed in the gastrointestinal tract where it is involved in enterocyte
differentiation. Oct-4, although first known as a transcription factor in embryonic stem cells, also plays a
role in sustaining self-renewal capacity of adult somatic stem cells and in regulating DNA repair genes.
Our finding that pasireotide activates the signal transduction pathways of both transcription factors via
SST3 and SST5 suggests that the mechanism of radioprotection not only involves amelioration of
gastrointestinal injury, but also the promotion of stem cell self-renewal, stem cell differentiation, and DNA
repair.
1;1
(PS7-41) Cyclin B1/CDK1 enhances mitochondrial bioenergetics in radiation response. Lili Qin, PhD MD
1;2
1
and Jian Jian Li, PhD MD ; University of California, Davis, Sacramento, CA and university of California,
Davis, Sacramento, CA
2
Mammalian cells can induce an adaptive response under a certain level of genotoxic stresses
including low dose ionizing radiation. The mechanisms underlying such adaptive radioprotection,
especially mitochondria-associated homeostasis, are poorly understood. In this study, we found that
human mammary epithelial cells (MCF-10A) exhibit enhanced mitochondria ATP production and oxygen
consumption with a peak at 24h after exposure to 5 Gy radiation along with increased level of
mitochondria superoxide. Similar alterations of mitochondria metabolism were found in human skin
keratinocytes (HK18) and mouse skin epithelia cells (JB6) with different peak times of mitochondrial
respiration. In addition, G2/M regulator Cyclin B1/CDK1 was found translocated to mitochondria of MCF-
10A cells after radiation as well as post-G2/M transition. The mitochondrial relocation of CyclinB1/CDK1
was linked with DNA repair and mitochondrial activation and dominant negative CDK1 targeted to
mitochondria reverses enhanced mitochondrial ATP production caused by mitochondria targeting wild-
type CDK1. Dramatically, cellular DNA damage repair capacity detected by H2AX foci formation was
374 | P a g e
