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25 pages, 6627 KiB

Open AccessArticle

Natural Merosesquiterpenes Activate the DNA Damage Response via DNA Strand Break Formation and Trigger Apoptotic Cell Death in p53-Wild-Type and Mutant Colorectal Cancer

by Apisada Jiso, Philipp Demuth, Madeleine Bachowsky, Manuel Haas, Nina Seiwert, Daniel Heylmann, Birgit Rasenberger, Markus Christmann, Lea Dietrich, Thomas Brunner, Riyanti, Till F. Schäberle, Anuchit Plubrukarn and Jörg Fahrer

Cancers 2021, 13(13), 3282; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133282 - 30 Jun 2021

Cited by 7 | Viewed by 2773

Abstract

Colorectal cancer (CRC) is a frequently occurring malignant disease with still low survival rates, highlighting the need for novel therapeutics. Merosesquiterpenes are secondary metabolites from marine sponges, which might be useful as antitumor agents. To address this issue, we made use of a [...] Read more.

Colorectal cancer (CRC) is a frequently occurring malignant disease with still low survival rates, highlighting the need for novel therapeutics. Merosesquiterpenes are secondary metabolites from marine sponges, which might be useful as antitumor agents. To address this issue, we made use of a compound library comprising 11 isolated merosesquiterpenes. The most cytotoxic compounds were smenospongine > ilimaquinone ≈ dactylospontriol, as shown in different human CRC cell lines. Alkaline Comet assays and γH2AX immunofluorescence microscopy demonstrated DNA strand break formation in CRC cells. Western blot analysis revealed an activation of the DNA damage response with CHK1 phosphorylation, stabilization of p53 and p21, which occurred both in CRC cells with p53 knockout and in p53-mutated CRC cells. This resulted in cell cycle arrest followed by a strong increase in the subG1 population, indicative of apoptosis, and typical morphological alterations. In consistency, cell death measurements showed apoptosis following exposure to merosesquiterpenes. Gene expression studies and analysis of caspase cleavage revealed mitochondrial apoptosis via BAX, BIM, and caspase-9 as the main cell death pathway. Interestingly, the compounds were equally effective in p53-wild-type and p53-mutant CRC cells. Finally, the cytotoxic activity of the merosesquiterpenes was corroborated in intestinal tumor organoids, emphasizing their potential for CRC chemotherapy. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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24 pages, 4570 KiB

Open AccessArticle

Oxaliplatin-Induced Senescence in Colorectal Cancer Cells Depends on p14^ARF-Mediated Sustained p53 Activation

by Maja T. Tomicic, Franziska Krämer, Alexandra Nguyen, Christian Schwarzenbach and Markus Christmann

Cancers 2021, 13(9), 2019; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092019 - 22 Apr 2021

Cited by 13 | Viewed by 3050

Abstract

Senescence is an important consequence of cytostatic drug-based tumor therapy. Here we analyzed to which degree the anticancer drug oxaliplatin induces cell death, cell cycle arrest, and senescence in colorectal cancer (CRC) cells and elucidated the role of p53. Oxaliplatin treatment resulted in [...] Read more.

Senescence is an important consequence of cytostatic drug-based tumor therapy. Here we analyzed to which degree the anticancer drug oxaliplatin induces cell death, cell cycle arrest, and senescence in colorectal cancer (CRC) cells and elucidated the role of p53. Oxaliplatin treatment resulted in the G2-phase arrest in all CRC lines tested (HCT116^p53+/+, HCT116^p53−/−, LoVo, SW48 and SW480). Immunoblot analysis showed that within the p53-competent lines p53 and p21^CIP1 are activated at early times upon oxaliplatin treatment. However, at later times, only LoVo cells showed sustained activation of the p53/p21^CIP1 pathway, accompanied by a strong induction of senescence as measured by senescence-associated β-Gal staining and induction of senescence-associated secretory phenotype (SASP) factors. Opposite to LoVo, the p53/p21^CIP1 response and senescence induction was much weaker in the p53-proficient SW48 and SW480 cells, which was due to deficiency for p14^ARF. Thus, among lines studied only LoVo express p14^ARF protein and siRNA-mediated knockdown of p14^ARF significantly reduced sustained p53/p21^CIP1 activation and senescence. Vice versa, ectopic p14^ARF expression enhanced oxaliplatin-induced senescence in SW48 and SW480 cells. Our data show that oxaliplatin-induced senescence in CRC cells is dependent on p53 proficiency; however, a significant induction can only be observed upon p14^ARF-mediated p53 stabilization. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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Review

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17 pages, 642 KiB

Open AccessReview

Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

by Maja T. Tomicic, Mona Dawood and Thomas Efferth

Cancers 2021, 13(16), 4072; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164072 - 13 Aug 2021

Cited by 11 | Viewed by 3594

Abstract

Colorectal cancer (CRC) belongs to the most common tumor types, and half of all CRC harbor missense mutations in the TP53 tumor suppressor gene. In addition to genetically caused loss of function of p53, epigenetic alterations (DNA methylation, histone modifications, micro-RNAs) contribute to [...] Read more.

Colorectal cancer (CRC) belongs to the most common tumor types, and half of all CRC harbor missense mutations in the TP53 tumor suppressor gene. In addition to genetically caused loss of function of p53, epigenetic alterations (DNA methylation, histone modifications, micro-RNAs) contribute to CRC development. In this review, we focused on epigenetic alterations related to the entire p53 signaling pathway upstream and downstream of p53. Methylation of genes which activate p53 function has been reported, and methylation of APC and MGMT was associated with increased mutation rates of TP53. The micro-RNA 34a activates TP53 and was methylated in CRC. Proteins that regulate TP53 DNA methylation, mutations, and acetylation of TP53-related histones were methylated in CRC. P53 regulates the activity of numerous downstream proteins. Even if TP53 is not mutated, the function of wildtype p53 may be compromised if corresponding downstream genes are epigenetically inactivated. Thus, the role of p53 for CRC development, therapy response, and survival prognosis of patients may be much more eminent than previously estimated. Therefore, we propose that novel diagnostic devices measuring the entirety of genetic and epigenetic changes in the “p53 signalome” have the potential to improve the predictive and prognostic power in CRC diagnostics and management. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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42 pages, 2634 KiB

Open AccessFeature PaperReview

p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies

by Anđela Horvat, Ana Tadijan, Ignacija Vlašić and Neda Slade

Cancers 2021, 13(12), 2885; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122885 - 09 Jun 2021

Cited by 8 | Viewed by 3919

Abstract

The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each [...] Read more.

The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each family member possesses two promoters and alternative translation initiation sites, and they undergo alternative splicing, generating multiple isoforms. The resulting isoforms have important roles in carcinogenesis, while their expression is dysregulated in several human tumors including colorectal carcinoma, which makes them potential targets in cancer treatment. Their activities arise, at least in part, from the ability to form tetramers that bind to specific DNA sequences and activate the transcription of target genes. In this review, we summarize the current understanding of the biological activities and regulation of the p53/p73 isoforms, highlighting their role in colorectal tumorigenesis. The analysis of the expression patterns of the p53/p73 isoforms in human cancers provides an important step in the improvement of cancer therapy. Furthermore, the interactions among the p53 family members which could modulate normal functions of the canonical p53 in tumor tissue are described. Lastly, we emphasize the importance of clinical studies to assess the significance of combining the deregulation of different members of the p53 family to define the outcome of the disease. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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24 pages, 1131 KiB

Open AccessReview

The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

by Maurice Michel, Leonard Kaps, Annett Maderer, Peter R. Galle and Markus Moehler

Cancers 2021, 13(10), 2296; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102296 - 11 May 2021

Cited by 44 | Viewed by 5861

Abstract

Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability [...] Read more.

Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. The carcinogenesis of CRC is based on a stepwise accumulation of mutations, leading either to an activation of oncogenes or a deactivation of suppressor genes. The loss of genetic stability triggers activation of proto-oncogenes (e.g., KRAS) and inactivation of tumor suppression genes, namely TP53 and APC, which together drive the transition from adenoma to adenocarcinoma. On the one hand, p53 mutations confer resistance to classical chemotherapy but, on the other hand, they open the door for immunotherapy, as p53-mutated tumors are rich in neoantigens. Aberrant function of the TP53 gene product, p53, also affects stromal and non-stromal cells in the tumor microenvironment. Cancer-associated fibroblasts together with other immunosuppressive cells become valuable assets for the tumor by p53-mediated tumor signaling. In this review, we address the manifold implications of p53 mutations in CRC regarding therapy, treatment response and personalized medicine. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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29 pages, 3758 KiB

Open AccessReview

The Role of p53 Signaling in Colorectal Cancer

by Magdalena C. Liebl and Thomas G. Hofmann

Cancers 2021, 13(9), 2125; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092125 - 28 Apr 2021

Cited by 110 | Viewed by 13465

Abstract

The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its [...] Read more.

The transcription factor p53 functions as a critical tumor suppressor by orchestrating a plethora of cellular responses such as DNA repair, cell cycle arrest, cellular senescence, cell death, cell differentiation, and metabolism. In unstressed cells, p53 levels are kept low due to its polyubiquitination by the E3 ubiquitin ligase MDM2. In response to various stress signals, including DNA damage and aberrant growth signals, the interaction between p53 and MDM2 is blocked and p53 becomes stabilized, allowing p53 to regulate a diverse set of cellular responses mainly through the transactivation of its target genes. The outcome of p53 activation is controlled by its dynamics, its interactions with other proteins, and post-translational modifications. Due to its involvement in several tumor-suppressing pathways, p53 function is frequently impaired in human cancers. In colorectal cancer (CRC), the TP53 gene is mutated in 43% of tumors, and the remaining tumors often have compromised p53 functioning because of alterations in the genes encoding proteins involved in p53 regulation, such as ATM (13%) or DNA-PKcs (11%). TP53 mutations in CRC are usually missense mutations that impair wild-type p53 function (loss-of-function) and that even might provide neo-morphic (gain-of-function) activities such as promoting cancer cell stemness, cell proliferation, invasion, and metastasis, thereby promoting cancer progression. Although the first compounds targeting p53 are in clinical trials, a better understanding of wild-type and mutant p53 functions will likely pave the way for novel CRC therapies. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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21 pages, 3659 KiB

Open AccessReview

Platinum Complexes in Colorectal Cancer and Other Solid Tumors

by Beate Köberle and Sarah Schoch

Cancers 2021, 13(9), 2073; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092073 - 25 Apr 2021

Cited by 40 | Viewed by 5705

Abstract

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to [...] Read more.

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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22 pages, 1869 KiB

Open AccessReview

Tumor Suppressor Protein p53 and Inhibitor of Apoptosis Proteins in Colorectal Cancer—A Promising Signaling Network for Therapeutic Interventions

by Ömer Güllülü, Stephanie Hehlgans, Claus Rödel, Emmanouil Fokas and Franz Rödel

Cancers 2021, 13(4), 624; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040624 - 04 Feb 2021

Cited by 20 | Viewed by 4562

Abstract

Despite recent advances in the treatment of colorectal cancer (CRC), patient’s individual response and clinical follow-up vary considerably with tumor intrinsic factors to contribute to an enhanced malignancy and therapy resistance. Among these markers, upregulation of members of the inhibitor of apoptosis protein [...] Read more.

Despite recent advances in the treatment of colorectal cancer (CRC), patient’s individual response and clinical follow-up vary considerably with tumor intrinsic factors to contribute to an enhanced malignancy and therapy resistance. Among these markers, upregulation of members of the inhibitor of apoptosis protein (IAP) family effects on tumorigenesis and radiation- and chemo-resistance by multiple pathways, covering a hampered induction of apoptosis/autophagy, regulation of cell cycle progression and DNA damage response. These mechanisms are tightly controlled by the tumor suppressor p53 and thus transcriptional and post-translational regulation of IAPs by p53 is expected to occur in malignant cells. By this, cellular IAP1/2, X-linked IAP, Survivin, BRUCE and LIVIN expression/activity, as well as their intracellular localization is controlled by p53 in a direct or indirect manner via modulating a multitude of mechanisms. These cover, among others, transcriptional repression and the signal transducer and activator of transcription (STAT)3 pathway. In addition, p53 mutations contribute to deregulated IAP expression and resistance to therapy. This review aims at highlighting the mechanistic and clinical importance of IAP regulation by p53 in CRC and describing potential therapeutic strategies based on this interrelationship. Full article

(This article belongs to the Special Issue The Tumor Suppressor TP53 in Colorectal Carcinoma)

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