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

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

doi:10.1016/j.tranon.2018.11.013

Cited by 9 publications

(9 citation statements)

References 43 publications

(55 reference statements)

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“…However, it was documented with these few cell lines that HPV‐positive cells are generally more sensitive to radiation as well as to cisplatin, when compared to HPV‐negative cells, which is in excellent agreement with the clinical data . The higher sensitivity of HPV‐positive cell lines cannot be attributed to a depressed p53/p21 activation as recently shown by us but rather to a defect in cell cycle regulation and repair of DNA double‐strand breaks (DSBs) . Recent data indicate that the defect in DSB repair might result from impaired homologous recombination (HR) .…”

Section: Introductionsupporting

confidence: 84%

HPV‐negative and HPV‐positive HNSCC cell lines show similar numerical but different structural chromosomal aberrations

et al. 2019

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Background It was tested whether the difference in carcinogenesis between noxa and human papillomavirus (HPV)‐driven head and neck squamous cell carcinoma (HNSCC) is associated with a variation in genomic instability. Methods Conventional and molecular cytogenetics in HPV‐positive and HPV‐negative HNSCC cell lines. Results Numerical aneuploidy determined by multicolor fluorescence in situ hybridization and DNA ploidy was very similar for both entities with most chromosomes being present either in quadruplicate or triplicate, and only few are still diploid with, however, a striking similarity in the overall pattern. A clear difference was seen concerning the translocations formed, with no difference in the total amount but with a significantly higher genomic instability of HPV‐positive cell lines at chromosome 3 as compared to HPV‐negative cells. Conclusion The different processes of carcinogenesis of HPV‐positive and HPV‐negative HNSCC appear to result in a similar pattern of numerical but a clear difference in structural chromosomal aberrations.

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Section: Introductionsupporting

confidence: 84%

HPV‐negative and HPV‐positive HNSCC cell lines show similar numerical but different structural chromosomal aberrations

et al. 2019

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“…The experiments presented here were performed with ten HNSCC cell lines, which were previously shown to be a good preclinical model to reflect the clinical response of these tumors, with HPV pos. HNSCC, exhibiting a much better response towards combined radiochemotherapy [24][25][26]43,44]. BEZ235 was found to abrogate basal phosphorylation of Akt1 at S473, at concentrations as low as 50 nM, and also to inhibit the radiation-induced activation of Akt1 at this site.…”

Section: Discussionmentioning

confidence: 95%

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining

Schötz

Balzer

Brandt

et al. 2020

Cancers

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The PI3K/Akt/mTOR pathway is frequently altered in human papillomavirus (HPV)-positive and negative squamous cell carcinoma of the head and neck (HNSCC) and overstimulation is associated with poor prognosis. PI3K drives Akt activation and constitutive signaling acts pro-proliferative, supports cell survival, DNA repair, and contributes to radioresistance. Since the small molecule NVP-BEZ235 (BEZ235) is a potent dual inhibitor of this pathway, we were interested whether BEZ235 could be an efficient radiosensitizer. The 50 nM BEZ235 was found to abrogate endogenous and irradiation-induced phosphorylation of Akt (Ser473). The anti-proliferative capacity of the drug resulted in an increase in G1-phase cells. Repair of radiation-induced DNA double-strand breaks (DSBs) was strongly suppressed. Reduction in DSB repair was only apparent in G1- but not in G2-phase cells, suggesting that BEZ235 primarily affects non-homologous end joining. This finding was confirmed using a DSB repair reporter gene assay and could be attributed to an impaired phosphorylation of DNA-PKcs (S2056). Cellular radiosensitivity increased strongly after BEZ235 addition in all HNSCC cell lines used, especially when irradiated in the G0 or G1 phase. Our data indicate that targeting the PI3K/Akt/mTOR pathway by BEZ235 with concurrent radiotherapy may be considered an effective strategy for the treatment of HNSCC, regardless of the HPV and Akt status.

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“…20 Other studies have suggested that bortezomib can liberate p53, contributing to apoptosis in HPV-positive HNSCC. 20,35 Chen et al were among the first to examine bortezomib in HNSCC cells and also demonstrated in vitro activity at nanomolar ranges. 36 Unfortunately, promising preclinical data have not translated into clinical activity using bortezomib.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis signaling molecules as treatment targets in head and neck squamous cell carcinoma

Thomas

Fulcher

et al. 2020

The Laryngoscope

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Objectives: To evaluate BCL-2 family signaling molecules in head and neck squamous cell carcinoma (HNSCC) and examine the ability of therapeutic agents with variable mechanisms of action to induce apoptosis in HNSCC cells. Methods: messenger ribonculeic acid (mRNA) expression of BAK, BAX, B-cell lymphoma (Bcl-2), BCL2 Like 1 (BCL2L1), and MCL1 were measured in The Cancer Genome Atlas (TCGA) head and neck cancer dataset, as well as in a dataset from a cohort at Montefiore Medical Center (MMC). Protein expression was similarly evaluated in a panel of HNSCC cell lines (HN30, HN31, HN5, MDA686LN, UMSCC47). Cell viability and Annexin V assays were used to assess the efficacy and apoptotic potential of a variety of agents (ABT-263 [navitoclax], A-1210477, and bortezomib. Results: Expression of BAK, BAX, BCL2L1, and MCL1 were each significantly higher than expression of BCL2 in the TCGA and MMC datasets. Protein expression demonstrated the same pattern of expression when examined in HNSCC cell lines. Treatment with combined ABT-263 (navitoclax)/A-1210477 or with bortezomib demonstrated apoptosis responses that approached or exceeded treatment with staurospaurine control. Conclusion: HNSCC cells rely on inhibition of apoptosis via BCL-xL and MCL-1 overexpression, and induction of apoptosis remains a potential therapeutic option as long as strategies overcome redundant anti-apoptotic signals.

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

Cited by 9 publications

References 43 publications

HPV‐negative and HPV‐positive HNSCC cell lines show similar numerical but different structural chromosomal aberrations

HPV‐negative and HPV‐positive HNSCC cell lines show similar numerical but different structural chromosomal aberrations

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining

Apoptosis signaling molecules as treatment targets in head and neck squamous cell carcinoma

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