Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines

Busch, Chia‐Jung; Becker, B; Kriegs, Malte; Gatzemeier, Fruzsina; Krüger, Katharina; Möckelmann, Nikolaus; Fritz, Gerhard; Petersen, Cordula; Knecht, Rainald; Rothkamm, Kai; Rieckmann, Thorsten

doi:10.18632/oncotarget.9028

Cited by 28 publications

(28 citation statements)

References 33 publications

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“…Collectively, our results demonstrated that ACHN‐shXPF cell presented impaired intra‐S‐phase checkpoint and more sub‐G1 population compare to that of ACHN‐shNC cell in response to cisplatin treatment, which together could explain the enhanced cisplatin sensitivity upon XPF knocking down. In support of this, previous studies have reported that loss of S‐phase arrest sensitizes cell to cisplatin‐induced DNA damage and cisplatin sensitive cells present more G2/M arrest than that of cisplatin resistant cells …”

Section: Resultssupporting

confidence: 65%

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Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma

Zhang

Shi

Yuan³

et al. 2016

Intl Journal of Cancer

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Human renal cancer is extremely resistant to chemotherapy and radiation therapy. This clinical characteristic reduces the efficacy of chemotherapeutic agents in the treatment of recurrence or metastasis following surgical resection. Understanding the mechanism of chemotherapy resistance in renal cell carcinoma remains a significant challenge. In this study, we have shown that varied level of XPF expression was organ-tissue specific by comparing human renal cancer, bladder cancer, testicular cancer and their normal tissue counterparts, respectively. The expression of XPF was significantly higher in renal cancer than in bladder cancer and testicular cancer and correlated with the clinical characteristic of their chemotherapeutics sensitivity. These novel findings proposed that the intrinsic chemoresistance of human renal cell carcinomas might be derived from the high level of XPF expression. In a panel of five cancer cell lines, decreasing cisplatin sensitivity correlated with increasing levels of XPF expression. Knockdown of XPF expression not only increased sensitivity of renal carcinoma cells to cisplatin treatment by affecting the DNA damage response, including DNA repair, cell cycle regulation and apoptosis, but also increased senescence of renal cancer cell. Furthermore, experiment in vivo confirmed that silenced XPF significantly increased the sensitivity and survival following treatment with cisplatin in xenograft mice bearing renal cell tumor. These findings firstly uncover a partial mechanism of intrinsic chemoresistance in renal cancer and may provide a new approach to break through the obstacle of intrinsic chemoresistance by targeting the XPF protein with a potential new inhibitor.

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Section: Resultssupporting

confidence: 65%

“…In support of this, previous studies have reported that loss of S-phase arrest sensitizes cell to cisplatin-induced DNA damage 21 and cisplatin sensitive cells present more G2/M arrest than that of cisplatin resistant cells. 22…”

Section: Knocking Down Xpf Significantly Altered the Dna Damage Respomentioning

confidence: 99%

Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma

Zhang

Shi

Yuan³

et al. 2016

Intl Journal of Cancer

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“…In published studies, different HPV-positive cell lines have shown considerable variations in sensitivity not only to irradiation 7,26,27 but also to cisplatin compared to HPV-negative cells 8,34 , and the same was observed in Figure 4. Cell cycle redistribution of HPV-negative (FaDu) and HPV-positive (2A3) cells after cisplatin (CDDP) treatment combined with single-dose (IR 2 Gy) (a) or fractionated irradiation (IR 3 × 2 Gy) (b).…”

Section: Discussionsupporting

confidence: 60%

“…In clinical practice, cisplatin adds a benefit to radiotherapy, with significant improvement of overall survival at five years in head and neck SCC patients 35,36 . It is known that cisplatin treatment increases the duration of S phase and arrests cells in the G 2 /M phase 8,34,[37][38][39] , which could contribute to radiosensitization. In the present study we share similar observations.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of cisplatin chemotherapy combined with fractionated radiotherapy regimen in HPV-positive and HPV-negative experimental pharyngeal squamous cell carcinoma

Kranjc

Prevc

Žakelj

et al. 2020

Sci Rep

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HPV infection renders oropharyngeal squamous cell carcinomas more radiosensitive, which results in a favorable prognosis for HPV-positive patients treated with radiation alone or with concurrent platinum-based chemotherapy. The degree of radiosensitivity in fractionated regimens has not yet been fully explored; therefore, in this study, the radiosensitivity of HPV-negative tumors (FaDu) was compared to that of HPV-positive tumors (2A3) subjected to concurrent cisplatin chemotherapy and fractionated versus isoeffective single-dose tumor irradiation in immunodeficient mice. HPV-positive tumors were approximately 5 times more radiosensitive than HPV-negative tumors, irrespective of the irradiation regimen. In both tumor models, concurrent cisplatin chemotherapy and the fractionated regimen induced significant tumor radiosensitization, with a 3-to 4-fold increase in the tumor growth delay compared to that of single-dose irradiation. Furthermore, the degree of radiosensitization induced by cisplatin chemotherapy concurrent with the fractionated irradiation regimen was much higher in HPV-positive tumors, where a synergistic antitumor effect was observed. Specifically, after combined therapy, a 26% higher survival rate was observed in mice with HPV-positive tumors than in mice with HPV-negative tumors. These data suggest that HPV-positive tumors are more radiosensitive to fractionated regimen than to single-dose irradiation with concurrent cisplatin chemotherapy acting synergistically to irradiation. HPV-positive squamous cell carcinoma (SCC) of the oropharynx is an increasingly common disease and is in many ways distinct from its HPV-negative counterpart, which is caused by smoking and excessive alcohol consumption 1. In the clinic, it was observed that HPV-positive oropharyngeal SCC responds better to treatment with radiotherapy and concurrent platinum-based chemotherapy 2,3. This observation was confirmed in a number of preclinical and clinical studies 2,4-10. Furthermore, the underlying mechanisms were explored. These studies suggested that the reason for the better response of HPV-positive SCC to the treatment may be impaired DNA damage repair in HPV-infected tumor cells 5-7. This impairment is probably caused by HPV-viral proteins, E6 and E7, which interfere with the host cell cycle to promote the reproduction of the virus 11-13. Furthermore, the immune response to viral proteins may contribute to better treatment outcomes in HPV-positive tumors, as the presence of HPV antigens may render the tumors more immunogenic 14 .

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“…Finally, E6 has also been reported to impair HR while E7 had no effect (38) and nonisogenic comparisons of 1 HPV− and 2 HPV+HNSCC cell lines have suggested HPV-associated defects in NHEJ (39) or HR (39,40) or both (39). However, when larger cell line panels of HPV+ (n = 6) and HPV− HNSCC (n = 5) cell lines were compared, no difference in cisplatin sensitivity has been noted, which is a surrogate for HR efficiency (41). To deconvolve these observations on DSB repair, we measured all 3 major DSB repair pathways (NHEJ, HR, and MMEJ) in 3 separate assay systems and found consistent E7-mediated suppression of NHEJ and promotion of MMEJ, which matches human-level evidence in HPV-associated cancer genomes.…”

Section: Discussionmentioning

confidence: 99%

Human papillomavirus 16 promotes microhomology-mediated end-joining

Leeman

Bell

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Squamous cell carcinomas (SCCs) arising from aerodigestive or anogenital epithelium that are associated with the human papillomavirus (HPV) are far more readily cured with radiation therapy than HPV-negative SCCs. The mechanism behind this increased radiosensitivity has been proposed to be secondary to defects in DNA repair, although the specific repair pathways that are disrupted have not been elucidated. To gain insight into this important biomarker of radiosensitivity, we first examined genomic patterns reflective of defects in DNA double-strand break repair, comparing HPV-associated and HPV-negative head and neck cancers (HNSCC). Compared to HPV-negative HNSCC genomes, HPV+ cases demonstrated a marked increase in the proportion of deletions with flanking microhomology, a signature associated with a backup, error-prone double-strand break repair pathway known as microhomology-mediated end-joining (MMEJ). Then, using 3 different methodologies to comprehensively profile double-strand break repair pathways in isogenic paired cell lines, we demonstrate that the HPV16 E7 oncoprotein suppresses canonical nonhomologous end-joining (NHEJ) and promotes error-prone MMEJ, providing a mechanistic rationale for the clinical radiosensitivity of these cancers.

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Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines

Cited by 28 publications

References 33 publications

Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma

Higher expression of XPF is a critical factor in intrinsic chemotherapy resistance of human renal cell carcinoma

Synergistic effect of cisplatin chemotherapy combined with fractionated radiotherapy regimen in HPV-positive and HPV-negative experimental pharyngeal squamous cell carcinoma

Human papillomavirus 16 promotes microhomology-mediated end-joining

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