Translational Oncology (Mar 2019)

In HPV-Positive HNSCC Cells, Functional Restoration of the p53/p21 Pathway by Proteasome Inhibitor Bortezomib Does Not Affect Radio- or Chemosensitivity

  • Steve Seltzsam,
  • Frank Ziemann,
  • Kristin Dreffke,
  • Stefanie Preising,
  • Andrea Arenz,
  • Ulrike Schötz,
  • Rita Engenhart-Cabillic,
  • Ekkehard Dikomey,
  • Andrea Wittig

Journal volume & issue
Vol. 12, no. 3
pp. 417 – 425

Abstract

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Human papillomavirus (HPV) associated squamous cell carcinomas of the head and neck region (HPV+ HNSCCs) harbor diverging biological features as compared to classical noxa-induced (HPV−) HNSCC. One striking difference between subtypes is that the tumor suppressor gene TP53 is usually not mutated in HPV+ HNSCCs. However, p53 is inhibited by viral oncoprotein E6, leading to premature proteasomal degradation. We asked whether bortezomib (BZM), a clinically approved inhibitor of the proteasome, can functionally restore p53 and investigated in how far this will result in an enhanced radio- or chemosensitivity of HPV+ HNSCC cell lines. For all four HPV+ cell lines tested, BZM led to functional restoration of p53 and transactivation of downstream protein p21. In HPV+ cells, BZM also restored the radiation-induced p53/p21 transactivation. Consistently, in HPV+ cells, a restored G1 arrest as well as enhanced apoptosis were seen when BZM was given prior to irradiation (IR) or cisplatin (CDDP). BZM alone reduced the clonogenic survival of both HPV− and HPV+ cells. However, if BZM was combined with IR or CDDP, BZM did not significantly enhance radio- or chemosensitivity of HPV+ or HPV− HNSCC cell lines.