Optimizing Phosphopeptide Structures That Target 14-3-3ε in Cutaneous Squamous Cell Carcinoma
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ABSTRACT:
SUBMITTER: Kamayirese S
PROVIDER: S-EPMC10795040 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:14-3-3ε is involved in various types of malignancies by increasing cell proliferation, promoting cell invasion or inhibiting apoptosis. In cutaneous squamous cell carcinoma (cSCC), 14-3-3ε is over expressed and mislocalized from the nucleus to the cytoplasm where it interacts with the cell division cycle 25 A (CDC25A) and suppresses apoptosis. Hence inhibition of the 14-3-3ε - CDC25A interaction is an attractive target for promoting apoptosis in cSCC. In this work, we optimized the structure of our previously designed inhibitor of 14-3-3ε - CDC25A interaction, pT, a phosphopeptide fragment corresponding to one of the two binding regions of CDC25A to 14-3-3ε. Starting from pT, we developed peptide analogs that bind 14-3-3ε with nanomolar affinities. Peptide analogs were designed by shortening the pT peptide, and introducing modifications at position 510 of the pT(502-510) analog. Both molecular dynamics (MD) simulations and biophysical methods were used to determine peptides binding to 14-3-3ε. Shortening the pT peptide from 14 to 9 amino acid residues resulted in a peptide (pT(502-510)) that binds 14-3-3ε with a KD value of 45.2 nM. Gly to Phe substitution in position 510 of pT(502-510) led to further improvement in affinity (KD: 22.0 nM) of the peptide for 14-3-3ε. Our results suggest that the designed peptide analogs are potential candidates for inhibiting 14-3-3ε -CDC25A interactions in cSCC cells; thus, inducing their apoptosis.
| S-EPMC10592926 | biostudies-literature
Project description:More than a million cases of cutaneous squamous cell carcinoma are diagnosed in the USA each year, and its incidence is increasing. Most of these malignancies arise from premalignant lesions, providing an opportunity for intervention before malignant progression. We previously documented how cytoplasmic mislocalization of CDC25A in premalignant and malignant skin cancers confers resistance to apoptotic cell death via a mechanism that depends on its interaction with 14-3-3ε. From these data, we hypothesized that 14-3-3ε overexpression drives skin tumor development and progression, such that targeting 14-3-3ε may be a useful strategy for skin cancer treatment. Like CDC25A, 14-3-3ε was overexpressed and mislocalized to the cytoplasm of both benign and malignant human skin cancer. Skin-targeted deletion of the 14-3-3ε gene reduced skin tumor development by 75% and blocked malignant progression. 14-3-3ε suppressed apoptosis through activation of Akt, leading to inhibition of BCL2 associated agonist of cell death and upregulation of Survivin. Using virtual tetrapeptide libraries, we developed a novel peptide that specifically blocked 14-3-3ε heterodimerization and thereby prevented its interaction with CDC25A. The peptide reduced prosurvival signaling, killed skin cancer cells and reduced skin tumor growth in xenograft. Normal skin keratinocytes were unaffected by inhibition or deletion of 14-3-3ε. Thus, targeting of 14-3-3ε dimerization is a promising strategy for the treatment of premalignant skin lesions.
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Project description:Hyperactive retrovirus-associated DNA sequence (Ras) genes have been found in human cancers and are involved in cancer pathogenesis. Salirasib, one anti-Ras compound, was reported to exhibit antitumoral effects, but its role remains unclear in cutaneous squamous cell carcinoma (cSCC). In our study, salirasib treatment led to deregulation of c-Raf, ERK and Akt signaling, blockage of MTOR signaling, interruption on Beclin 1-related autophagy regulation, activation of apoptosis and down-regulation of some cell cycle regulatory proteins in primary human epidermal keratinocyte (HEK)s, but did not exhibit similar effects in the human cSCC cell line COLO-16. MEK inhibitor U0126 can lead to dephosphorylation of MTOR and Rictor in COLO-16 cells; however, c-Raf was not yet down-regulated after salirasib treatment in the presence of U0126. Furthermore, we verified that the Ras activity could be suppressed by salirasib, and there was no loss-of-function mutation in c-Raf in HEKs and COLO-16 cells. In summary, salirasib does not exhibit antitumoral effects in the cSCC cells in assays in vitro. We speculated that the disability of signaling transmission from Ras to c-Raf in COLO-16 cells might contribute to the ineffective performance of salirasib.
| S-EPMC6160676 | biostudies-literature
Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, and its incidence is rising because of the aging population. Nectin cell adhesion molecule 4 (NECTIN4) is involved in the progression of tumors and has attracted interest as a potential therapeutic target. However, little is known about the expression and significance of NECTIN4 in cSCC. The aim of this study was to determine the expression and function of NECTIN4 in cSCC. Immunohistological NECTIN4 expression was investigated in tissues from 34 cSCC patients. Using an A431 human SCC cell line, the role of NECTIN4 in the regulation of cell-cell attachment and migration and proliferation was assessed. NECTIN4 was expressed in most cSCC tissues and on the plasma membrane of A431 cells. Silencing of NECTIN4 prevented cell-cell attachment and induced the expression migration-related molecules, leading to an increase in cell migration. Knockdown of NECTIN4 downregulated extracellular signal-regulated kinase signaling, decreased cyclin D1 expression, and inhibited cell proliferation. These results show that NECTIN4 is expressed in cSCC and functions in the regulation of cell-cell interactions, as well as in the migration and proliferation of SCC cells. NECTIN4-targeted therapy may serve as a novel and promising treatment for cSCC.
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Project description: Not available
| S-EPMC11367778 | biostudies-literature
Project description:Non-melanoma skin cancers are cutaneous malignancies representing the most common form of cancer in the United States. They are comprised predominantly of basal cell carcinomas and squamous cell carcinomas (cSCC). The incidence of cSCC is increasing, resulting in substantial morbidity and ever higher treatment costs; currently in excess of one billion dollars, per annum. Here, we review research defining the molecular basis and development of cSCC that aims to provide new insights into pathogenesis and drive the development of novel, cost and morbidity saving therapies.
| S-EPMC8998533 | biostudies-literature
Project description:Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer with high mortality rates in the advanced stage. Chronic inflammation is a recognized risk factor for cSCC progression and the complement system, as a part of innate immunity, belongs to the microenvironment of tumors. The complement system is a double-edged sword in cancer, since complement activation is involved in anti-tumor cytotoxicity and immune responses, but it also promotes cancer progression directly and indirectly. Recently, the role of several complement components and inhibitors in the regulation of progression of cSCC has been shown. In this review, we will discuss the role of complement system components and inhibitors as biomarkers and potential new targets for therapeutic intervention in cSCC.
| S-EPMC6678994 | biostudies-literature
Project description:Our objective is exploring the therapeutic potential of itraconazole in cSCC and investigate its molecular mechanism.Transcriptomic and proteomic analyses were used to explore the underlying anti-cancer mechanism.
2022-04-01 | PXD030984 | Pride
Project description:TAp63 is a transcription factor belonging to the p53 family with important tumor suppressive functions. We show that TAp63-/- mice exhibit an increased susceptibility to UVR-induced cutaneous squamous cell carcinoma (cuSCC). These tumors showed global disruption of miRNA and mRNA expression when compared to tumors arising in wild-type mice. A comparison to similarly sequenced human cuSCC tumors identified miR-30c-2* and miR-497 as being significantly underexpressed in cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and xenografts. Proteomic profiling of cells transfected with either miRNA showed significant downregulation of proteins related to cell cycle progression and mitosis. A cross-platform comparison of the RNAseq and proteomics signatures identified 7 downregulated proteins, which are also frequently overexpressed in both mouse and human cuSCC. Knockdown of AURKA, KIF18B, PKMYT1, and ORC1 in cuSCC cell lines suppressed tumor cell proliferation and induced cell death. Additionally, we found that an investigational, oral, selective inhibitor of AURKA suppressed cuSCC cell growth and induced cell death, and showed anti-tumor effects in vivo. Our data establishes TAp63 as an essential regulator of miRNA expression during skin carcinogenesis and reveals a novel network of miRNAs and mRNAs, which include potential targets for therapeutic intervention.
2020-07-07 | PXD014261 | Pride
Project description:PurposeCancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.Experimental designWe explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing.ResultsWe show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women.ConclusionsThis work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.
| S-EPMC7613610 | biostudies-literature