Since the bi-allelic inactivation of both neurofibromin 1 (NF1) gene alleles (NF1(-/-)) in Schwann cells (SCs) is common in both benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type 1 (NF1), other genetic alterations in SCs may be required for tumor progression of PNs to MPNSTs. We found that the anti-apoptotic Bcl-xL protein is upregulated in MPNST tissues compared to PN tissues from patients with NF1 by immunohistological staining. In addition, we investigated whether Bcl-xL is upregulated in SCs derived from MPNSTs and found a significantly higher Bcl-xL expression level in sNF96.2 MPNST-derived SCs compared to normal human SCs (HSCs). We also discovered that the increased Bcl-xL expression caused an increase in drug resistance to doxorubicin in MPNST-derived SCs. Manipulation of NF1 gene expression levels by treatment with small interfering RNA (siRNA) and overexpression of the neurofibromin GAP-related domain (NF1-GRD) demonstrated that upregulated Bcl-xL expression in MPNST-derived SCs was caused by NF1 deficiency. Treatment with the Erk1/2 inhibitor, PD98059, resulted in a slight increase in Bcl-xL levels in neurofibromin-depleted normal HSCs, indicating that Bcl-xL upregulation in MPNST-derived SCs is mediated by activated Erk1/2, which is a Ras downstream protein regulated by neurofibromin. As the reduction of Bcl-xL expression restored sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, we examined the effect of the small molecule Bcl-xL inhibitor ABT-737 on sNF96.2 cells. A very low dose of ABT-737 combined with doxorubicin synergistically enhanced sensitivity to doxorubicin-induced apoptosis in sNF96.2 cells, suggesting that ABT-737 and doxorubicin may be a good combination to effectively treat NF1-associated MPNSTs with minimal side-effects. Collectively, our results suggest that upregulation of Bcl-xL in MPNST-derived SCs may be caused by the NF1 deficiency-mediated elevation in Ras/MAPK signaling and may provide a new potential chemotherapeutic target in patients with NF1 and MPNSTs.
机构:
Japan Sci & Technol Agcy, CREST, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Arima, Yoshimi
;
Hayashi, Hidemi
论文数: 0引用数: 0
h-index: 0
机构:
Link Genom Inc, Dept Biomed Res & Dev, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Hayashi, Hidemi
;
Kamata, Kanako
论文数: 0引用数: 0
h-index: 0
机构:
Link Genom Inc, Dept Biomed Res & Dev, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Kamata, Kanako
;
Goto, Takaaki M.
论文数: 0引用数: 0
h-index: 0
机构:Keio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Goto, Takaaki M.
;
Sasaki, Mikako
论文数: 0引用数: 0
h-index: 0
机构:Keio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Sasaki, Mikako
;
Kuramochi, Akira
论文数: 0引用数: 0
h-index: 0
机构:
Saitama Med Univ, Dept Dermatol, Saitama, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Kuramochi, Akira
;
Saya, Hideyuki
论文数: 0引用数: 0
h-index: 0
机构:
Keio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Japan Sci & Technol Agcy, CREST, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
机构:
Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
Univ Alabama Birmingham, Med Scientist Training Program, Birmingham, AL 35294 USAUniv Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
brossier, Nicole M.
;
Carroll, Steven L.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL 35294 USAUniv Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
机构:
Univ Alabama Birmingham, Div Neuropathol, Dept Pathol, Birmingham, AL 35294 USAUniv Alabama Birmingham, Div Neuropathol, Dept Pathol, Birmingham, AL 35294 USA
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Chai, Guolin
;
Liu, Ning
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Liu, Ning
;
Ma, Junrong
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Ma, Junrong
;
Li, Hua
论文数: 0引用数: 0
h-index: 0
机构:Maine Inst Human Genet & Hlth, Bangor, ME USA
Li, Hua
;
Oblinger, Janet L.
论文数: 0引用数: 0
h-index: 0
机构:
Nationwide Childrens Hosp, Dept Pediat, Res Inst, Columbus, OH USA
Nationwide Childrens Hosp, Dept Otolaryngol, Res Inst, Columbus, OH USA
Ohio State Univ, Columbus, OH 43210 USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Oblinger, Janet L.
;
Prahalad, Agasanur K.
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Prahalad, Agasanur K.
;
Gong, Meng
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Gong, Meng
;
Chang, Long-Sheng
论文数: 0引用数: 0
h-index: 0
机构:
Nationwide Childrens Hosp, Dept Pediat, Res Inst, Columbus, OH USA
Nationwide Childrens Hosp, Dept Otolaryngol, Res Inst, Columbus, OH USA
Ohio State Univ, Columbus, OH 43210 USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Chang, Long-Sheng
;
Wallace, Margaret
论文数: 0引用数: 0
h-index: 0
机构:Maine Inst Human Genet & Hlth, Bangor, ME USA
Wallace, Margaret
;
Muir, David
论文数: 0引用数: 0
h-index: 0
机构:
Univ Florida, Dept Pediat, Gainesville, FL USA
Univ Florida, Dept Neurosci, Gainesville, FL 32610 USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Muir, David
;
Guha, Abhijit
论文数: 0引用数: 0
h-index: 0
机构:
Univ Hlth Network, Toronto Western Hosp, Alan & Susan Hudson Chair Neurooncol, Dept Surg, Toronto, ON, Canada
Univ Toronto, Hosp Sick Children, Res Inst, Arthur & Sonia Labatts Brain Tumor Ctr, Toronto, ON, CanadaMaine Inst Human Genet & Hlth, Bangor, ME USA
Guha, Abhijit
;
Phipps, Roger J.
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Phipps, Roger J.
;
Hock, Janet M.
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Hock, Janet M.
;
Yu, Xijie
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
机构:
Jackson Lab, Bar Harbor, ME 04609 USA
Whitehead Inst Biomed Res, Cambridge, MA 02142 USAJackson Lab, Bar Harbor, ME 04609 USA
Dai, Chengkai
;
Santagata, Sandro
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USAJackson Lab, Bar Harbor, ME 04609 USA
Santagata, Sandro
;
Tang, Zijian
论文数: 0引用数: 0
h-index: 0
机构:
Jackson Lab, Bar Harbor, ME 04609 USAJackson Lab, Bar Harbor, ME 04609 USA
Tang, Zijian
;
Shi, Jiayuan
论文数: 0引用数: 0
h-index: 0
机构:
Jackson Lab, Bar Harbor, ME 04609 USAJackson Lab, Bar Harbor, ME 04609 USA
Shi, Jiayuan
;
Cao, Junxia
论文数: 0引用数: 0
h-index: 0
机构:
Jackson Lab, Bar Harbor, ME 04609 USAJackson Lab, Bar Harbor, ME 04609 USA
Cao, Junxia
;
Kwon, Hyoungtae
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USAJackson Lab, Bar Harbor, ME 04609 USA
Kwon, Hyoungtae
;
Bronson, Roderick T.
论文数: 0引用数: 0
h-index: 0
机构:
Tufts Univ, Dept Pathol, Sch Med & Vet Med, Boston, MA 02111 USAJackson Lab, Bar Harbor, ME 04609 USA
Bronson, Roderick T.
;
Whitesell, Luke
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USAJackson Lab, Bar Harbor, ME 04609 USA
Whitesell, Luke
;
Lindquist, Susan
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
MIT, Howard Hughes Med Inst, Cambridge, MA USA
MIT, Dept Biol, Cambridge, MA USAJackson Lab, Bar Harbor, ME 04609 USA
机构:
Japan Sci & Technol Agcy, CREST, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Arima, Yoshimi
;
Hayashi, Hidemi
论文数: 0引用数: 0
h-index: 0
机构:
Link Genom Inc, Dept Biomed Res & Dev, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Hayashi, Hidemi
;
Kamata, Kanako
论文数: 0引用数: 0
h-index: 0
机构:
Link Genom Inc, Dept Biomed Res & Dev, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Kamata, Kanako
;
Goto, Takaaki M.
论文数: 0引用数: 0
h-index: 0
机构:Keio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Goto, Takaaki M.
;
Sasaki, Mikako
论文数: 0引用数: 0
h-index: 0
机构:Keio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Sasaki, Mikako
;
Kuramochi, Akira
论文数: 0引用数: 0
h-index: 0
机构:
Saitama Med Univ, Dept Dermatol, Saitama, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Kuramochi, Akira
;
Saya, Hideyuki
论文数: 0引用数: 0
h-index: 0
机构:
Keio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
Japan Sci & Technol Agcy, CREST, Tokyo, JapanKeio Univ, Sch Med, Div Gene Regulat, Inst Adv Med Res,Shinjuku Ku, Tokyo 1608582, Japan
机构:
Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
Univ Alabama Birmingham, Med Scientist Training Program, Birmingham, AL 35294 USAUniv Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
brossier, Nicole M.
;
Carroll, Steven L.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
Univ Alabama Birmingham, Dept Neurobiol, Birmingham, AL 35294 USAUniv Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
机构:
Univ Alabama Birmingham, Div Neuropathol, Dept Pathol, Birmingham, AL 35294 USAUniv Alabama Birmingham, Div Neuropathol, Dept Pathol, Birmingham, AL 35294 USA
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Chai, Guolin
;
Liu, Ning
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Liu, Ning
;
Ma, Junrong
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Ma, Junrong
;
Li, Hua
论文数: 0引用数: 0
h-index: 0
机构:Maine Inst Human Genet & Hlth, Bangor, ME USA
Li, Hua
;
Oblinger, Janet L.
论文数: 0引用数: 0
h-index: 0
机构:
Nationwide Childrens Hosp, Dept Pediat, Res Inst, Columbus, OH USA
Nationwide Childrens Hosp, Dept Otolaryngol, Res Inst, Columbus, OH USA
Ohio State Univ, Columbus, OH 43210 USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Oblinger, Janet L.
;
Prahalad, Agasanur K.
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Prahalad, Agasanur K.
;
Gong, Meng
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Gong, Meng
;
Chang, Long-Sheng
论文数: 0引用数: 0
h-index: 0
机构:
Nationwide Childrens Hosp, Dept Pediat, Res Inst, Columbus, OH USA
Nationwide Childrens Hosp, Dept Otolaryngol, Res Inst, Columbus, OH USA
Ohio State Univ, Columbus, OH 43210 USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Chang, Long-Sheng
;
Wallace, Margaret
论文数: 0引用数: 0
h-index: 0
机构:Maine Inst Human Genet & Hlth, Bangor, ME USA
Wallace, Margaret
;
Muir, David
论文数: 0引用数: 0
h-index: 0
机构:
Univ Florida, Dept Pediat, Gainesville, FL USA
Univ Florida, Dept Neurosci, Gainesville, FL 32610 USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Muir, David
;
Guha, Abhijit
论文数: 0引用数: 0
h-index: 0
机构:
Univ Hlth Network, Toronto Western Hosp, Alan & Susan Hudson Chair Neurooncol, Dept Surg, Toronto, ON, Canada
Univ Toronto, Hosp Sick Children, Res Inst, Arthur & Sonia Labatts Brain Tumor Ctr, Toronto, ON, CanadaMaine Inst Human Genet & Hlth, Bangor, ME USA
Guha, Abhijit
;
Phipps, Roger J.
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Phipps, Roger J.
;
Hock, Janet M.
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
Hock, Janet M.
;
Yu, Xijie
论文数: 0引用数: 0
h-index: 0
机构:
Maine Inst Human Genet & Hlth, Bangor, ME USAMaine Inst Human Genet & Hlth, Bangor, ME USA
机构:
Jackson Lab, Bar Harbor, ME 04609 USA
Whitehead Inst Biomed Res, Cambridge, MA 02142 USAJackson Lab, Bar Harbor, ME 04609 USA
Dai, Chengkai
;
Santagata, Sandro
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USAJackson Lab, Bar Harbor, ME 04609 USA
Santagata, Sandro
;
Tang, Zijian
论文数: 0引用数: 0
h-index: 0
机构:
Jackson Lab, Bar Harbor, ME 04609 USAJackson Lab, Bar Harbor, ME 04609 USA
Tang, Zijian
;
Shi, Jiayuan
论文数: 0引用数: 0
h-index: 0
机构:
Jackson Lab, Bar Harbor, ME 04609 USAJackson Lab, Bar Harbor, ME 04609 USA
Shi, Jiayuan
;
Cao, Junxia
论文数: 0引用数: 0
h-index: 0
机构:
Jackson Lab, Bar Harbor, ME 04609 USAJackson Lab, Bar Harbor, ME 04609 USA
Cao, Junxia
;
Kwon, Hyoungtae
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USAJackson Lab, Bar Harbor, ME 04609 USA
Kwon, Hyoungtae
;
Bronson, Roderick T.
论文数: 0引用数: 0
h-index: 0
机构:
Tufts Univ, Dept Pathol, Sch Med & Vet Med, Boston, MA 02111 USAJackson Lab, Bar Harbor, ME 04609 USA
Bronson, Roderick T.
;
Whitesell, Luke
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USAJackson Lab, Bar Harbor, ME 04609 USA
Whitesell, Luke
;
Lindquist, Susan
论文数: 0引用数: 0
h-index: 0
机构:
Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
MIT, Howard Hughes Med Inst, Cambridge, MA USA
MIT, Dept Biol, Cambridge, MA USAJackson Lab, Bar Harbor, ME 04609 USA