Page 156 - 2014 Printable Abstract Book
P. 156
exposure. The changes in the mutant fraction values were also compared to the changes in the number
(and quality) of chromosome aberrations in the same time periods.
(PS2-36) Tumor suppressor protein DAB2IP participates in spindle assembly checkpoint and maintains
1
1
1; 3
chromosomal stability in PCa cells. Lan Yu ; Zeng-Fu Shang ; Jer-Tsong Hsieh 2; 3; 4 ; Benjamin Chen ; and
Debabrata Saha, 1; 3 Department of Radiation Oncology, University of Texas Southwestern Medical Center,
1
2
Dallas, TX ; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX ;
3
Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center, Dallas, TX ;
and Department of Oncology, National Taiwan University Hospital, National Taiwan University College of
Medicine, Taipei, Taiwan
4
DAB2IP, a tumor suppressor protein, is known to inhibit the PI3K-Akt pro-survival pathway and
enhance ASK1 mediated apoptosis in prostate cancer (PCa) cells. Decreased expression of DAB2IP is often
detected in advanced PCa patients and associated with poor prognosis. This loss of DAB2IP is primarily
due to altered epigenetic regulation of its promoter. DAB2IP deficiency in PCa cells also lead to radiation
resistance, increased DNA repair ability and decreased apoptosis after radiation therapy.
Our ongoing studies reveal a novel role of DAB2IP in modulating the spindle assembly checkpoint (SAC).
SAC prevents the premature separation of the duplicated chromosomes until each chromosome is
properly attached to the spindle microtubules through the formation of mitotic checkpoint complex
(MCC) and by inhibiting Cdc20, an activator of the anaphase-promoting APC/C E3 ubiquitin ligase complex.
Here, we report that DAB2IP directly interacts with Cdc20 and prevent its degradation in prometaphase.
In the absence of DAB2IP, untimely degradation of Cdc20 promotes turnover of MCC-APC/C complex and
contributes to premature mitotic exit even in the presence of microtubule toxic drug nocodazole and
paclitaxel. Consistent with this observation, we also found increased chromosomal instability in DAB2IP
deficient PCa cells. In conclusion, a novel function of DAB2IP on mitotic SAC regulation is identified which
is essential for maintaining chromosomal stability and cancer prevention.
(PS2-37) Age dependent effect of fast neutrons on rat mammary carcinogenesis. Tatsuhiko Imaoka,
1
1
1
1;2
1
PhD ; Mayumi Nishimura ; Kazuhiro Daino, PhD ; Ayaka Hosoki, PhD ; Masaru Takabatake, M.R.S. ; Kaye
1;2
1
1
Showler, B.R.S. ; Toshiaki Kokubo, D.V.M., PhD ; and Yoshiya Shimada, PhD, National Institute of
2
1
Radiological Sciences, Chiba, Japan and Tokyo Metropolitan University, Tokyo, Japan
Exposure of children to neutrons can be met in occasions such as proton radiotherapy and
intensity-modulated radiotherapy for treatment of childhood tumors, as these modalities emit secondary
neutrons from irradiation apparatuses and the patient body. The mammary gland is one of the susceptible
organs to radiation carcinogenesis, and can be exposed to neutrons during radiotherapy for thoracic
tumors. We therefore aimed to investigate the effect of neutrons during childhood on the risk of
mammary carcinogenesis. Female Sprague-Dawley rats of 1, 3 and 7 weeks after birth (neonatal,
prepubertal and postpubertal stages, respectively) were whole-body irradiated with fast neutrons, having
an average energy of 2 MeV, at a dose of 0.05, 0.1, 0.2, 0.5 or 1.0 Gy. Rats were observed until 90 weeks
of age and the hazard ratio for mammary carcinoma development, as compared to the non-irradiated
group, was calculated based on palpation records and pathological examination, using Cox’s proportional
hazard model. Hazard ratios for γ-ray-induced carcinogenesis were obtained from our previous study, in
154 | P a g e
(and quality) of chromosome aberrations in the same time periods.
(PS2-36) Tumor suppressor protein DAB2IP participates in spindle assembly checkpoint and maintains
1
1
1; 3
chromosomal stability in PCa cells. Lan Yu ; Zeng-Fu Shang ; Jer-Tsong Hsieh 2; 3; 4 ; Benjamin Chen ; and
Debabrata Saha, 1; 3 Department of Radiation Oncology, University of Texas Southwestern Medical Center,
1
2
Dallas, TX ; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX ;
3
Simmons Comprehensive Cancer Center University of Texas Southwestern Medical Center, Dallas, TX ;
and Department of Oncology, National Taiwan University Hospital, National Taiwan University College of
Medicine, Taipei, Taiwan
4
DAB2IP, a tumor suppressor protein, is known to inhibit the PI3K-Akt pro-survival pathway and
enhance ASK1 mediated apoptosis in prostate cancer (PCa) cells. Decreased expression of DAB2IP is often
detected in advanced PCa patients and associated with poor prognosis. This loss of DAB2IP is primarily
due to altered epigenetic regulation of its promoter. DAB2IP deficiency in PCa cells also lead to radiation
resistance, increased DNA repair ability and decreased apoptosis after radiation therapy.
Our ongoing studies reveal a novel role of DAB2IP in modulating the spindle assembly checkpoint (SAC).
SAC prevents the premature separation of the duplicated chromosomes until each chromosome is
properly attached to the spindle microtubules through the formation of mitotic checkpoint complex
(MCC) and by inhibiting Cdc20, an activator of the anaphase-promoting APC/C E3 ubiquitin ligase complex.
Here, we report that DAB2IP directly interacts with Cdc20 and prevent its degradation in prometaphase.
In the absence of DAB2IP, untimely degradation of Cdc20 promotes turnover of MCC-APC/C complex and
contributes to premature mitotic exit even in the presence of microtubule toxic drug nocodazole and
paclitaxel. Consistent with this observation, we also found increased chromosomal instability in DAB2IP
deficient PCa cells. In conclusion, a novel function of DAB2IP on mitotic SAC regulation is identified which
is essential for maintaining chromosomal stability and cancer prevention.
(PS2-37) Age dependent effect of fast neutrons on rat mammary carcinogenesis. Tatsuhiko Imaoka,
1
1
1
1;2
1
PhD ; Mayumi Nishimura ; Kazuhiro Daino, PhD ; Ayaka Hosoki, PhD ; Masaru Takabatake, M.R.S. ; Kaye
1;2
1
1
Showler, B.R.S. ; Toshiaki Kokubo, D.V.M., PhD ; and Yoshiya Shimada, PhD, National Institute of
2
1
Radiological Sciences, Chiba, Japan and Tokyo Metropolitan University, Tokyo, Japan
Exposure of children to neutrons can be met in occasions such as proton radiotherapy and
intensity-modulated radiotherapy for treatment of childhood tumors, as these modalities emit secondary
neutrons from irradiation apparatuses and the patient body. The mammary gland is one of the susceptible
organs to radiation carcinogenesis, and can be exposed to neutrons during radiotherapy for thoracic
tumors. We therefore aimed to investigate the effect of neutrons during childhood on the risk of
mammary carcinogenesis. Female Sprague-Dawley rats of 1, 3 and 7 weeks after birth (neonatal,
prepubertal and postpubertal stages, respectively) were whole-body irradiated with fast neutrons, having
an average energy of 2 MeV, at a dose of 0.05, 0.1, 0.2, 0.5 or 1.0 Gy. Rats were observed until 90 weeks
of age and the hazard ratio for mammary carcinoma development, as compared to the non-irradiated
group, was calculated based on palpation records and pathological examination, using Cox’s proportional
hazard model. Hazard ratios for γ-ray-induced carcinogenesis were obtained from our previous study, in
154 | P a g e
