Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

Chemotherapy is intended to induce cancer cell death through apoptosis and other avenues. Unfortunately, as discussed in this article, moderate doses of genotoxic drugs such as cisplatin typical of those achieved in the clinic often invoke a cytostatic/dormancy rather than cytotoxic/apoptosis response in solid tumour-derived cell lines. This is commonly manifested by an extended apoptotic threshold, with extensive apoptosis only being seen after very high/supralethal doses of such agents. The dormancy response can be associated with senescence-like features, polyploidy and/or multinucleation, depending in part on the p53 status of the cells. In most solid tumour-derived cells, dormancy represents a long-term survival mechanism, ultimately contributing to disease recurrence. This review highlights the nonlinearity of key aspects of the molecular and cellular responses to bulky DNA lesions in human cells treated with chemotherapeutic drugs (e.g., cisplatin) or ultraviolet light-C (a widely used tool for unraveling details of the DNA damage-response) as a function of the level of genotoxic stress. Such data highlight the growing realization that targeting dormant cancer cells, which frequently emerge following conventional anticancer treatments, may represent a novel strategy to prevent or, at least, significantly suppress cancer recurrence.

Download Full-text

The poly(ADP-ribose)-dependent chromatin remodeler Alc1 induces local chromatin relaxation upon DNA damage

Molecular Biology of the Cell ◽

10.1091/mbc.e16-05-0269 ◽

2016 ◽

Vol 27 (24) ◽

pp. 3791-3799 ◽

Cited By ~ 56

Author(s):

Hafida Sellou ◽

Théo Lebeaupin ◽

Catherine Chapuis ◽

Rebecca Smith ◽

Anna Hegele ◽

...

Keyword(s):

Dna Damage ◽

Structural Changes ◽

Cellular Responses ◽

Dna Lesions ◽

Fast Kinetics ◽

Important Player ◽

Chromatin Relaxation ◽

Kinetics Of ◽

Laser Microirradiation

Chromatin relaxation is one of the earliest cellular responses to DNA damage. However, what determines these structural changes, including their ATP requirement, is not well understood. Using live-cell imaging and laser microirradiation to induce DNA lesions, we show that the local chromatin relaxation at DNA damage sites is regulated by PARP1 enzymatic activity. We also report that H1 is mobilized at DNA damage sites, but, since this mobilization is largely independent of poly(ADP-ribosyl)ation, it cannot solely explain the chromatin relaxation. Finally, we demonstrate the involvement of Alc1, a poly(ADP-ribose)- and ATP-dependent remodeler, in the chromatin-relaxation process. Deletion of Alc1 impairs chromatin relaxation after DNA damage, while its overexpression strongly enhances relaxation. Altogether our results identify Alc1 as an important player in the fast kinetics of the NAD+- and ATP-dependent chromatin relaxation upon DNA damage in vivo.

Download Full-text

Interferon-Stimulated Gene 15 in the Control of Cellular Responses to Genotoxic Stress

Molecules and Cells ◽

10.14348/molcells.2017.0027 ◽

2017 ◽

Vol 40 (2) ◽

pp. 83-89 ◽

Cited By ~ 14

Author(s):

Young Joo Jeon ◽

Jong Ho Park ◽

Chin Ha Chung

Keyword(s):

Genotoxic Stress ◽

Cellular Responses ◽

Interferon Stimulated Gene 15

Download Full-text

MORC2 regulates DNA damage response through a PARP1-dependent pathway

Nucleic Acids Research ◽

10.1093/nar/gkz545 ◽

2019 ◽

Vol 47 (16) ◽

pp. 8502-8520 ◽

Cited By ~ 4

Author(s):

Lin Zhang ◽

Da-Qiang Li

Keyword(s):

Dna Damage ◽

Zinc Finger ◽

Chromatin Remodeling ◽

Dna Damage Response ◽

Mammalian Cells ◽

Cellular Response ◽

Genotoxic Stress ◽

Underlying Mechanism ◽

Dna Lesions ◽

Damage Response

Abstract Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling enzyme with an emerging role in DNA damage response (DDR), but the underlying mechanism remains largely unknown. Here, we show that poly(ADP-ribose) polymerase 1 (PARP1), a key chromatin-associated enzyme responsible for the synthesis of poly(ADP-ribose) (PAR) polymers in mammalian cells, interacts with and PARylates MORC2 at two residues within its conserved CW-type zinc finger domain. Following DNA damage, PARP1 recruits MORC2 to DNA damage sites and catalyzes MORC2 PARylation, which stimulates its ATPase and chromatin remodeling activities. Mutation of PARylation residues in MORC2 results in reduced cell survival after DNA damage. MORC2, in turn, stabilizes PARP1 through enhancing acetyltransferase NAT10-mediated acetylation of PARP1 at lysine 949, which blocks its ubiquitination at the same residue and subsequent degradation by E3 ubiquitin ligase CHFR. Consequently, depletion of MORC2 or expression of an acetylation-defective PARP1 mutant impairs DNA damage-induced PAR production and PAR-dependent recruitment of DNA repair proteins to DNA lesions, leading to enhanced sensitivity to genotoxic stress. Collectively, these findings uncover a previously unrecognized mechanistic link between MORC2 and PARP1 in the regulation of cellular response to DNA damage.

Download Full-text

Redundancy of mammalian Y family DNA polymerases in cellular responses to genomic DNA lesions induced by ultraviolet light

Nucleic Acids Research ◽

10.1093/nar/gku779 ◽

2014 ◽

Vol 42 (17) ◽

pp. 11071-11082 ◽

Cited By ~ 23

Author(s):

Jacob G. Jansen ◽

Piya Temviriyanukul ◽

Niek Wit ◽

Frédéric Delbos ◽

Claude-Agnès Reynaud ◽

...

Keyword(s):

Ultraviolet Light ◽

Genomic Dna ◽

Dna Polymerases ◽

Cellular Responses ◽

Dna Lesions ◽

Y Family

Download Full-text

Impact of postoperative complications on disease recurrence and long-term survival following oesophagogastric cancer resection

British Journal of Surgery ◽

10.1002/bjs.11318 ◽

2019 ◽

Vol 107 (1) ◽

pp. 103-112 ◽

Cited By ~ 4

Author(s):

J. H. Saunders ◽

F. Yanni ◽

M. S. Dorrington ◽

C. R. Bowman ◽

R. S. Vohra ◽

...

Keyword(s):

Postoperative Complications ◽

Disease Recurrence ◽

Term Survival ◽

Long Term Survival ◽

Cancer Resection ◽

Oesophagogastric Cancer

Download Full-text

Prognostic Variables and Surgical Management of Foot Melanoma: Review of a 25-Year Institutional Experience

ISRN Dermatology ◽

10.5402/2011/384729 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Omar M. Rashid ◽

Julia C. Schaum ◽

Luke G. Wolfe ◽

Nooshin K. Brinster ◽

James P. Neifeld

Keyword(s):

Surgical Management ◽

Disease Recurrence ◽

Demographic Characteristics ◽

Superficial Spreading ◽

Prognostic Variables ◽

Term Survival ◽

Aggressive Management ◽

Academic Center ◽

Institutional Experience

Introduction. Cutaneous foot melanoma is rare, challenging to manage, and not adequately examined in the literature. This study evaluated the prognostic variables and surgical management of foot melanoma. Materials and Methods. Foot melanoma cases managed at an academic center from 1985 to 2010 were retrospectively reviewed. Results. 46 patients were identified with a broad range of demographic characteristics. Overall recurrence was 32.6%: 19% acral lentiginous, 57% nodular, 66% superficial spreading, 30% melanoma unspecified, 50% severely atypical; 53% ulcerated, 23% nonulcerated; 29% on the dorsum of the foot, 17% heel, 60% ankle, 22% toe, 50% plantar; 0% <1 mm thick, 47% 1–4 mm, 33% >4 mm. 13 had positive nodes, 4 (31%) of whom recurred. Prognostic factors and recurrence did not correlate, and survival was 96% with a median followup of 91 months. Conclusions. Aggressive management of foot melanoma may result in excellent long-term survival even following disease recurrence.

Download Full-text

A novel strategy for identifying mutations that sensitize Drosophila eye development to caffeine and hydroxyurea

Genome ◽

10.1139/g06-098 ◽

2006 ◽

Vol 49 (11) ◽

pp. 1416-1427 ◽

Cited By ~ 2

Author(s):

E.A. Silva ◽

B.J. Lee ◽

L.S. Caceres ◽

D. Renouf ◽

B.R. Vilay ◽

...

Keyword(s):

Gene Function ◽

Imaginal Disc ◽

Essential Gene ◽

Cellular Responses ◽

Multiple Alleles ◽

Gene Mutant ◽

Nonessential Gene ◽

Disc Cells ◽

Complementation Groups ◽

Novel Strategy

This report describes a novel strategy for isolating Drosophila mutants with conditional eye phenotypes that should be generally applicable for identifying genes required for cellular responses to specific drugs. To test the strategy, we screened 3 of the 5 major chromosome arms for hydroxyurea- and (or) caffeine-sensitive (huc) mutants, and isolated mutations affecting 5 different complementation groups. Most of these were represented by single alleles; however, we also isolated multiple alleles of huc29DE gene, an essential gene that is also associated with a nonconditional pupal lethal phenotype. We also identified huc95E mutants, which are extremely sensitive to caffeine. Although huc95E is a nonessential gene, mutant imaginal disc cells undergo caffeine-dependent apoptosis, and huc95E gene function is required for the viability of the organism when mutant larvae are exposed to levels of caffeine that controls can easily tolerate. We have mapped the cytological positions of huc29D and huc95E as a first step toward molecularly characterizing the relevant genes.

Download Full-text

The recurrence patterns and post-recurrence survivals in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with preoperative paclitaxel/cisplatin-based chemoradiotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.80 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 80-80

Author(s):

Hung-Yang Kuo ◽

Jhe-Cyuan Guo ◽

Ta-Chen Huang ◽

Chia-Chi Lin ◽

Min-Shu Hsieh ◽

...

Keyword(s):

Distant Metastasis ◽

Locally Advanced ◽

Disease Recurrence ◽

Regional Recurrence ◽

Recurrence Pattern ◽

Term Survival ◽

Distant Failure ◽

Phase Ii Clinical Trials ◽

Kaplan Meier ◽

Recurrence Patterns

80 Background: More than half of patients (pts) with locally advanced ESCC would have disease recurrence after curative preoperative chemoradiation (CRT) followed by surgery. Whether recurrence pattern correlates with the post-recurrence survival remains uncertain. Methods: We included 131 pts with locally advanced ESCC (clinical T3N0-1M0 or T1-3N1M0 or M1a according to AJCC 6thedition) who were enrolled in 3 phase II clinical trials of preoperative CRT followed by surgery and had successfully completed CRT and surgery. These pts received preoperative twice weekly paclitaxel/cisplatin-based CRT with radiotherapy 40Gy given in 20 fractions followed by esophagectomy. When pts had first disease recurrence, we divided them into three groups according to their recurrence patterns: loco-regional recurrence (LRR), distant metastasis only (DM), and both LRR and DM (LRR+DM). Survival outcomes were compared using the Kaplan-Meier curves. Results: With a median follow-up of 34.8 months, 75 pts (57.3%) had disease recurrence (Table 1) and the median post-recurrence survival of these pts is 6.7 months (m). Among them, 24 pts (32.0%) had LRR, 19 (25.3%) pts had DM, and 32 pts (42.7%) had LRR+DM. There is no statistical difference of the post-recurrence survivals (Fig. 1) among 3 groups (5.4, 7.5, 4.9m, p = 0.43 in LRR, DM, and LRR+DM group respectively). It is noteworthy that 4 pts in the DM group with limited distant metastasis (1 had brain metastasis, 3 had lung metastasis) had long post-recurrence survival (56.2+, 51.6+, 13.8+, 13.1+m) after receiving metastasectomy with or without chemotherapy. Conclusions: The post-recurrencesurvival of locally advanced ESCC pts who received preoperative CRT followed by surgerywere similar regardless of recurrence pattern (loco-regional recurrence or both loco-regional and distant failure). However, in pts with limited metastasis, curative metastasectomy might provide the opportunity of achieving long-term survival. (The work was supported by the Grant of MOST 103-2314-B-002-092, MOST 104-2314-B-002-111- and HCH104-024)

Download Full-text

The role of routine surveillance imaging in detecting oral cavity cancer recurrence in asymptomatic patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18561 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18561-e18561

Author(s):

Jeffrey Chi ◽

Su Yun Chung ◽

Carlos Alberto Lopez ◽

Douglas K. Frank ◽

Lucio Pereira ◽

...

Keyword(s):

Clinical Symptoms ◽

Residual Disease ◽

Cancer Recurrence ◽

Retrospective Chart Review ◽

Disease Recurrence ◽

Post Treatment ◽

Definitive Treatment ◽

Curative Intent ◽

Asymptomatic Patients ◽

Surveillance Imaging

e18561 Background: The optimal surveillance approach for patients who were definitively treated for oral squamous cell carcinoma (OSCC) is unclear, but it includes physical exams (PE) and surveillance imaging (SI) studies at intervals that vary amongst institutions. At our institution, patients are seen in office and underwent PE monthly for the first 3-6 months then every 3 months thereafter. SI is performed every 3 months during the first 2 years, every 6 months till year 4, and yearly thereafter. Concerning symptoms or findings resulting from PE or SI may trigger further tests including biopsies as deemed necessary by treating team. In this study, we investigated value of SI in detecting recurrence of OSCC. Methods: Retrospective chart review was performed for the patients who were diagnosed with OSCC from 2014 to 2017 at our institution. Eligible patients included those who underwent definitive treatment (surgery, chemotherapy, radiation) of OSCC with curative intent. Patients without evidence of disease on post treatment imaging were included. Results: Two hundred OSCC patients were treated definitively. 138 (69%) patients had local disease and 62 (31%) patients had regional disease. 183 patients (%) had no clinical evidence of disease on post treatment baseline imaging. Patients who had residual disease on post-to scab were excluded from further analysis. The median follow-up was 29 months. 2-year overall survival was 87.4%. 82 patients underwent biopsy for suspicious findings and 44 patients had confirmed recurrence. 37 (84.1%) of the recurrences occurred in the first two years. 28 (63.6%) of recurrences were local, 13 (29.5%) were regional and 3 (6.8%) were metastases. 31 (70.6%) of patients with disease recurrence presented with clinical symptoms or had suspicious findings on PE. 13 (29.4%) of the recurrences were detected by SI alone (PPV=54.2 %) in asymptomatic patients most of which (92.3%) occurred within first 2 years. Conclusions: Majority of OSCC recurrence were detected due to clinical symptoms or positive findings on PE. However, 29.4% of recurrences were detected by SI alone in asymptomatic patients suggesting a role for SI for the first 2 years post-treatment of OSCC. Larger prospective studies are needed to determine the optimal frequency of SI.

Download Full-text