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Short half-life of HPV16 E6 and E7 mRNAs sensitizes HPV16-positive tonsillar cancer cell line HN26 to DNA-damaging drugs

Wu, Chengjun LU ; Nilsson, Kersti LU ; Zheng, Yunji LU ; Ekenstierna, Camilla LU ; Sugiyama, Natsuki LU ; Forslund, Ola LU ; Kajitani, Naoko LU ; Yu, Haoran LU ; Wennerberg, Johan LU and Ekblad, Lars LU , et al. (2019) In International Journal of Cancer 144(2). p.297-310
Abstract

Here we show that treatment of the HPV16-positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan-induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down-regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1-negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as... (More)

Here we show that treatment of the HPV16-positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan-induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down-regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1-negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half-life of the HPV16 E6 and E7 mRNAs renders HPV16-driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.

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publication status
published
subject
keywords
apoptosis, melphalan, p53, papillomavirus, tonsillar cancer
in
International Journal of Cancer
volume
144
issue
2
pages
297 - 310
publisher
John Wiley & Sons
external identifiers
  • scopus:85056308773
  • pmid:30303514
ISSN
0020-7136
DOI
10.1002/ijc.31918
language
English
LU publication?
yes
id
4093da0a-3b1e-47cf-af7e-97f6de3d936a
date added to LUP
2018-11-23 07:54:34
date last changed
2020-01-13 01:12:44
@article{4093da0a-3b1e-47cf-af7e-97f6de3d936a,
  abstract     = {<p>Here we show that treatment of the HPV16-positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan-induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down-regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1-negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half-life of the HPV16 E6 and E7 mRNAs renders HPV16-driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.</p>},
  author       = {Wu, Chengjun and Nilsson, Kersti and Zheng, Yunji and Ekenstierna, Camilla and Sugiyama, Natsuki and Forslund, Ola and Kajitani, Naoko and Yu, Haoran and Wennerberg, Johan and Ekblad, Lars and Schwartz, Stefan},
  issn         = {0020-7136},
  language     = {eng},
  number       = {2},
  pages        = {297--310},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  title        = {Short half-life of HPV16 E6 and E7 mRNAs sensitizes HPV16-positive tonsillar cancer cell line HN26 to DNA-damaging drugs},
  url          = {http://dx.doi.org/10.1002/ijc.31918},
  doi          = {10.1002/ijc.31918},
  volume       = {144},
  year         = {2019},
}