Page 272 - 2014 Printable Abstract Book
P. 272
over 12 days with a 5-days-on 2-days-off clinical schedule. Tumors were harvested 2-5 days post
treatment. Non-irradiated tumors were normalized to the same start volume as irradiated tumors and
allowed to grow until they reached terminal criterion. 20 Gy was sub-curative in this tumor model and
comparable growth delays were seen between PRT and SRT. Once harvested, tumors were fixed in PFA
and embedded in paraffin wax. Immunohistochemical analysis demonstrated a significant increase
(p<0.05) in CAIX expression in tumors irradiated with SRT when compared to controls. Increased tumor
hypoxia correlated with a significant increase (p<0.02) in VEGF expression in tumors irradiated with SRT
(n=7) when compared to non-irradiated controls (n=8). Conversely, tumors irradiated with PRT did not
show a significant increase in either VEGF or CAIX expression as compared to controls (n=7 and 3;
+
respectively). CD133 hematopoietic stem and progenitor cells were found to localize to areas of
radiation-induced DNA damage. These results support the hypothesis that PRT and SRT irradiation induce
different tumor microenvironments with respect to hypoxia. SRT was found to induce a hypoxic tumor
environment resulting in increased VEGF expression, a response known to induce angiogenesis and tumor
re-growth. Treatment with PRT induced a less hypoxic response compared with SRT, which may lead to
long-term treatment benefit in patients. These results demonstrate that different radiation schemes may
elicit different tumor responses.
(PS4-64) Activation of p53 and PI3-kinase by ionizing radiation induces the neuronal differentiation of
1
2
1
1
Neuro-2a cells. Sung-Kee Jo ; Heon-Soo Eom, MS ; Hae-Ran Park, PhD ; Changjong Moon, PhD, DVM ;
1
2
Sung-Ho Kim, PhD, DVM ; and Uhee Jung, PhD, Korea Atomic Energy Research Institute, Jeongeup-Si,
1
2
Korea, Republic of and Chonnam National University, Gwangju, Korea, Republic of
It is well known that ionizing radiation can cause neural stem cell damage and neuro-inflammation
leading to the suppression of neurogenesis, but the influences of ionizing radiation on neuronal
differentiation are not well defined. Therefore, we investigated the effects of IR on the neuronal
differentiation of Neuro-2a mouse neuroblastoma cells and the underlying signaling pathways. Irradiation
(4-16 Gy) induced the neuronal differentiation of neuro2-a cells as evidenced by the increases of neurite
outgrowth, neuronal marker expression (NeuN, Map2), and neurite formation-associated gene expression
(GAP-43, Rab13). However, the IR-induced neurite outgrowth was significantly attenuated when p53 was
inhibited by PFT-α or p53-siRNA. The IR-induced expression of NeuN and Map2 was also significantly
ameliorated by p53 inhibition. Then the upstream mediators of p53 activation in neuronal differentiation
including MEK, PKA, PI3K and p38 were examined for the involvement in IR-induced neuronal
differentiation. Only PI3K inhibitor, LY294002, suppressed the IR-induced neurite outgrowth, while the
inhibitors of MEK, PKA and p38 had no effect. Also, the treatment of LY294002 decreased the activation
of p53 and AKT. The expression of neurite formation-associated genes (GAP-43, Rab13). These results
suggest that IR is able to trigger the neurite outgrowth and neuronal differentiation in Neuro-2a cells and
the activation of p53 via PI3K may be an important step for IR-induced differentiation of Neuro-2a cells.
270 | P a g e
treatment. Non-irradiated tumors were normalized to the same start volume as irradiated tumors and
allowed to grow until they reached terminal criterion. 20 Gy was sub-curative in this tumor model and
comparable growth delays were seen between PRT and SRT. Once harvested, tumors were fixed in PFA
and embedded in paraffin wax. Immunohistochemical analysis demonstrated a significant increase
(p<0.05) in CAIX expression in tumors irradiated with SRT when compared to controls. Increased tumor
hypoxia correlated with a significant increase (p<0.02) in VEGF expression in tumors irradiated with SRT
(n=7) when compared to non-irradiated controls (n=8). Conversely, tumors irradiated with PRT did not
show a significant increase in either VEGF or CAIX expression as compared to controls (n=7 and 3;
+
respectively). CD133 hematopoietic stem and progenitor cells were found to localize to areas of
radiation-induced DNA damage. These results support the hypothesis that PRT and SRT irradiation induce
different tumor microenvironments with respect to hypoxia. SRT was found to induce a hypoxic tumor
environment resulting in increased VEGF expression, a response known to induce angiogenesis and tumor
re-growth. Treatment with PRT induced a less hypoxic response compared with SRT, which may lead to
long-term treatment benefit in patients. These results demonstrate that different radiation schemes may
elicit different tumor responses.
(PS4-64) Activation of p53 and PI3-kinase by ionizing radiation induces the neuronal differentiation of
1
2
1
1
Neuro-2a cells. Sung-Kee Jo ; Heon-Soo Eom, MS ; Hae-Ran Park, PhD ; Changjong Moon, PhD, DVM ;
1
2
Sung-Ho Kim, PhD, DVM ; and Uhee Jung, PhD, Korea Atomic Energy Research Institute, Jeongeup-Si,
1
2
Korea, Republic of and Chonnam National University, Gwangju, Korea, Republic of
It is well known that ionizing radiation can cause neural stem cell damage and neuro-inflammation
leading to the suppression of neurogenesis, but the influences of ionizing radiation on neuronal
differentiation are not well defined. Therefore, we investigated the effects of IR on the neuronal
differentiation of Neuro-2a mouse neuroblastoma cells and the underlying signaling pathways. Irradiation
(4-16 Gy) induced the neuronal differentiation of neuro2-a cells as evidenced by the increases of neurite
outgrowth, neuronal marker expression (NeuN, Map2), and neurite formation-associated gene expression
(GAP-43, Rab13). However, the IR-induced neurite outgrowth was significantly attenuated when p53 was
inhibited by PFT-α or p53-siRNA. The IR-induced expression of NeuN and Map2 was also significantly
ameliorated by p53 inhibition. Then the upstream mediators of p53 activation in neuronal differentiation
including MEK, PKA, PI3K and p38 were examined for the involvement in IR-induced neuronal
differentiation. Only PI3K inhibitor, LY294002, suppressed the IR-induced neurite outgrowth, while the
inhibitors of MEK, PKA and p38 had no effect. Also, the treatment of LY294002 decreased the activation
of p53 and AKT. The expression of neurite formation-associated genes (GAP-43, Rab13). These results
suggest that IR is able to trigger the neurite outgrowth and neuronal differentiation in Neuro-2a cells and
the activation of p53 via PI3K may be an important step for IR-induced differentiation of Neuro-2a cells.
270 | P a g e
