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11 pages, 6781 KiB

Open AccessArticle

Identification and In Vivo Validation of Unique Anti-Oncogenic Mechanisms Involving Protein Kinase Signaling and Autophagy Mediated by the Investigational Agent PV-10

by Son Tran, Patrick Sipila, Satbir Thakur, Chunfen Zhang and Aru Narendran

Cancers 2024, 16(8), 1520; https://doi.org/10.3390/cancers16081520 - 16 Apr 2024

Viewed by 779

Abstract

PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 [...] Read more.

PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 activity and its mechanisms against phenotypically and molecularly diverse adult solid tumors had not been conducted. In a panel of human cell lines derived from breast, colorectal, head and neck, and testicular cancers, we demonstrated that PV-10 induces cytotoxicity by apoptotic and autophagic pathways involving caspase-mediated PARP cleavage, downregulation of SQSTM1/p62, and upregulation of beclin-1. Treatment with PV-10 also consistently reduced phosphorylation of WNK1, which has been implicated in cancer cell migration and autophagy inhibition. By wound healing assay, PV-10 treatment inhibited the migration of cancer cells. Finally, significant inhibition of tumor growth was also noted in tumor-bearing mice treated with PV-10 by intralesional or systemic administration. In addition to known PV-10-mediated tumor-specific cytotoxic effects, we identified the mechanisms of PV-10 and provide new insights into its effect on autophagy and metastasis. Our data provide essential mechanism-based evidence and biomarkers of activity to formulate clinical studies of PV-10 in the future. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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14 pages, 1867 KiB

Open AccessArticle

Expression and Activity of the NF-κB Subunits in Chronic Lymphocytic Leukaemia: A Role for RelB and Non-Canonical Signalling

by Evan A. Mulligan, Susan J. Tudhope, Jill E. Hunter, Arabella E. G. Clift, Sarah L. Elliott, Geoffrey P. Summerfield, Jonathan Wallis, Chris J. Pepper, Barabara Durkacz, Stephany Veuger and Elaine Willmore

Cancers 2023, 15(19), 4736; https://doi.org/10.3390/cancers15194736 - 26 Sep 2023

Viewed by 971

Abstract

Background: Canonical NF-κB signalling by p65 (RelA) confers chemo-resistance and poor survival in chronic lymphocytic leukaemia (CLL). The role of non-canonical NF-κB signalling (leading to RelB and p52 subunit activation) in CLL is less understood, but given its importance in other B-cell tumour [...] Read more.

Background: Canonical NF-κB signalling by p65 (RelA) confers chemo-resistance and poor survival in chronic lymphocytic leukaemia (CLL). The role of non-canonical NF-κB signalling (leading to RelB and p52 subunit activation) in CLL is less understood, but given its importance in other B-cell tumour types, we theorised that RelB and p52 may also contribute to the pathology of CLL. Methods: DNA binding activity of all five NF-kB subunits, p65, p50, RelB, p52, and c-Rel, was quantified using ELISA and correlated to ex vivo chemoresistance, CD40L-stimulated signalling (to mimic the lymph node microenvironment), and clinical data. Results: Importantly, we show for the first time that high basal levels of RelB DNA binding correlate with nuclear RelB protein expression and are associated with del(11q), ATM dysfunction, unmutated IGHV genes, and shorter survival. High levels of nuclear p65 are prevalent in del(17p) cases (including treatment-naïve patients) and also correlate with the outcome. CD40L-stimulation resulted in rapid RelB activation, phosphorylation and processing of p100, and subsequent CLL cell proliferation. Conclusions: These data highlight a role for RelB in driving CLL cell tumour growth in a subset of patients and therefore strategies designed to inhibit non-canonical NF-κB signalling represent a novel approach that will have therapeutic benefit in CLL. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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11 pages, 1227 KiB

Open AccessArticle

Clinical Utility of Comprehensive Genomic Profiling in Patients with Unresectable Hepatocellular Carcinoma

by Shun Ishido, Kaoru Tsuchiya, Yoshihito Kano, Yutaka Yasui, Kenta Takaura, Naoki Uchihara, Keito Suzuki, Yuki Tanaka, Haruka Miyamoto, Michiko Yamada, Hiroaki Matsumoto, Tsubasa Nobusawa, Taisei Keitoku, Shohei Tanaka, Chiaki Maeyashiki, Nobuharu Tamaki, Yuka Takahashi, Hiroyuki Nakanishi, Urara Sakurai, Yasuhiro Asahina, Ryuichi Okamoto, Masayuki Kurosaki and Namiki Izumi Show full author list Hide full author list

Cancers 2023, 15(3), 719; https://doi.org/10.3390/cancers15030719 - 24 Jan 2023

Cited by 2 | Viewed by 1785

Abstract

This study aimed to investigate the clinical usefulness of comprehensive genomic profiling (CGP) in patients with unresectable hepatocellular carcinoma who received multiple systemic therapies in real-world practice. In this study, all nine patients had gene alterations, and seven were candidates eligible for clinical [...] Read more.

This study aimed to investigate the clinical usefulness of comprehensive genomic profiling (CGP) in patients with unresectable hepatocellular carcinoma who received multiple systemic therapies in real-world practice. In this study, all nine patients had gene alterations, and seven were candidates eligible for clinical trials based on the results of CGP. The median number of alterations per patient was four, and the blood sample was used in five patients with extrahepatic metastasis. We revealed the genomic information of the patients who received multiple systemic therapies and reported the utility of blood samples in patients with extrahepatic metastasis. Furthermore, the genomic status in patients treated with multiple molecular-targeted agents, including checkpoint inhibitors, would contribute to developing newer systemic agents. The molecular mechanism of hepatocellular carcinoma (HCC) is partially demonstrated. Moreover, in the patients receiving multiple molecular-targeted therapies, the gene alternations are still unknown. Six molecular-targeted therapies of unresectable HCC (uHCC) and comprehensive genomic profiling (CGP) have been approved in clinical practice. Hence, the utility of CGP in patients with uHCC treated with multiple molecular-targeted agents is investigated. The data of the patients with uHCC who received CGP tests were collected, retrospectively, between February 2021 and May 2022. Gene alterations detected by foundation testing, excluding variants of unknown significance, were reported in all nine patients. The samples for CGP were derived from liver tumor biopsy (n = 2), surgical specimens of bone metastases (n = 2), and blood (n = 5). The median number of systemic therapies was four. Seven patients were candidates eligible for clinical trials. One patient with a high tumor mutation burden (TMB) could receive pembrolizumab after CGP. This study presented genomic alternations after receiving multiple molecular-targeted therapies. However, further investigation needs to be conducted to develop personalized therapies and invent newer agents for treating HCC. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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19 pages, 6105 KiB

Open AccessArticle

Activation of OSM-STAT3 Epigenetically Regulates Tumor-Promoting Transcriptional Programs in Cervical Cancer

by Junho Noh, Chaelin You, Keunsoo Kang and Kyuho Kang

Cancers 2022, 14(24), 6090; https://doi.org/10.3390/cancers14246090 - 10 Dec 2022

Viewed by 2049

Abstract

Despite improvements in preventative strategies, such as regular screenings with Pap tests and human papillomavirus (HPV) tests as well as HPV vaccinations, effective treatment for advanced cervical cancer remains poor. Deregulation of STAT3 is an oncogenic factor that promotes tumorigenesis and epithelial-to-mesenchymal transition [...] Read more.

Despite improvements in preventative strategies, such as regular screenings with Pap tests and human papillomavirus (HPV) tests as well as HPV vaccinations, effective treatment for advanced cervical cancer remains poor. Deregulation of STAT3 is an oncogenic factor that promotes tumorigenesis and epithelial-to-mesenchymal transition (EMT) in various cancers. Oncostatin M (OSM), a pleiotropic cytokine, induces STAT3 activation, exacerbating cervical cancer. However, the mechanism by which the OSM-STAT3 axis epigenetically regulates tumor-progression-related genes in cervical cancer is not well understood. Here, we show that OSM-mediated STAT3 activation promotes pro-tumorigenic gene expression programs, with chromatin remodeling in cervical cancer. Reanalysis of scRNA-seq data performed in cervical cancer uncovered an interaction between the oncostatin M receptor (OSMR) on tumor cells and OSM induced by tumor-associated macrophages (TAMs). Our gene expression profiling (bulk RNA-seq) shows that OSM-induced genes were involved in hypoxia, wound healing, and angiogenesis, which were significantly inhibited by SD-36, a STAT3-selective degrader. Additionally, ATAC-seq experiments revealed that STAT3 binding motifs were preferentially enriched in open chromatin regions of the OSM-STAT3-regulated genes. Among the 50 candidate genes that were regulated epigenetically through the OSM-STAT3 axis, we found that the expression levels of NDRG1, HK2, PLOD2, and NPC1 were significantly correlated with those of OSMR and STAT3 in three independent cervical cancer cohorts. Also, higher expression levels of these genes are significantly associated with poor prognosis in cervical cancer patients. Collectively, our findings demonstrate that the OSM-STAT3 signaling pathway regulates crucial transcriptomic programs through epigenetic changes and that selective inhibition of STAT3 may be a novel therapeutic strategy for patients with advanced cervical cancer. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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18 pages, 3323 KiB

Open AccessArticle

Guggulsterone Induces Apoptosis in Multiple Myeloma Cells by Targeting High Mobility Group Box 1 via Janus Activated Kinase/Signal Transducer and Activator of Transcription Pathway

by Sabah Akhtar, Lubna Zarif, Shilpa Kuttikrishnan, Kirti S. Prabhu, Kalyani Patil, Sabah Nisar, Haissam Abou-Saleh, Maysaloun Merhi, Said Dermime, Ajaz A. Bhat and Shahab Uddin

Cancers 2022, 14(22), 5621; https://doi.org/10.3390/cancers14225621 - 16 Nov 2022

Cited by 4 | Viewed by 1775

Abstract

Multiple myeloma (MM) is a hematological disorder characterized by the abnormal expansion of plasma cells in the bone marrow. Despite great advances over the past three decades in discovering the efficacious therapies for MM, the disease remains incurable for most patients owing to [...] Read more.

Multiple myeloma (MM) is a hematological disorder characterized by the abnormal expansion of plasma cells in the bone marrow. Despite great advances over the past three decades in discovering the efficacious therapies for MM, the disease remains incurable for most patients owing to emergence of drug-resistant cancerous cells. Guggulsterone (GS), a phytosteroid, extracted from the gum resin of guggul plant, has displayed various anticancer activities in vitro and in vivo; however, the molecular mechanisms of its anticancer activity have not been evaluated in MM cells. Therefore, in this study, we investigated the anticancer activity of GS in various MM cell lines (U266, MM.1S, and RPMI 8226) and the mechanisms involved. GS treatment of MM cells caused inhibition of cell proliferation and induction of apoptotic cell death as indicated by increased Bax protein expression, activation of caspases, and cleavage of poly (ADP-ribose) polymerase. This was associated with the downregulation of various proliferative and antiapoptotic gene products, including cyclin D, Bcl-2, Bcl-xL, and X-linked inhibitor of apoptosis protein. GS also suppressed the constitutive and interleukin 6-induced activation of STAT3. Interestingly, the inhibition of Janus activated kinase or STAT3 activity by the specific inhibitors or by siRNA knockdown of STAT3 resulted in the downregulation of HMGB1, suggesting an association between GS, STAT3, and HMGB1. Finally, GS potentiated the anticancer effects of bortezomib (BTZ) in MM cells. Herein, we demonstrated that GS could be a potential therapeutic agent for the treatment of MM, possibly alone or in combination with BTZ. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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16 pages, 5650 KiB

Open AccessArticle

Farnesoid X Receptor Overexpression Decreases the Migration, Invasion and Angiogenesis of Human Bladder Cancers via AMPK Activation and Cholesterol Biosynthesis Inhibition

by Chien-Rui Lai, Yu-Ling Tsai, Wen-Chiuan Tsai, Tzu-Min Chen, Hsin-Han Chang, Chih-Ying Changchien, Sheng-Tang Wu, Hisao-Hsien Wang, Ying Chen and Yu-Huei Lin

Cancers 2022, 14(18), 4398; https://doi.org/10.3390/cancers14184398 - 09 Sep 2022

Cited by 7 | Viewed by 1720

Abstract

Bladder cancer is one of the most prevailing cancers worldwide. Although treatments for urothelial carcinoma have improved, the rate of recurrence observed in the clinic is still high. The aim of this study was to evaluate whether cholesterol biosynthesis is involved in the [...] Read more.

Bladder cancer is one of the most prevailing cancers worldwide. Although treatments for urothelial carcinoma have improved, the rate of recurrence observed in the clinic is still high. The aim of this study was to evaluate whether cholesterol biosynthesis is involved in the effect of Farnesoid X Receptor (FXR) on bladder cancers. FXR overexpression contributed to activation of 5′ AMP-activated protein kinase (AMPK) and decreased cholesterol levels. FXR overexpression reduced cholesterol biosynthesis and secretion by downregulating Sterol Regulatory Element Binding Protein 2 (SREBP2) and 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) expression. In addition, an AMPK inhibitor, dorsomorphin, reversed the inhibition of migration, invasion and angiogenesis by FXR overexpression. In a metastatic xenograft animal study, FXR overexpression suppressed bladder cancer lung metastasis by decreasing matrix metalloproteinase-2 (MMP2), SREBP2 and HMGCR expression. Moreover, FXR overexpression combined with atorvastatin treatment further enhanced the downregulation of the migratory, adhesive, invasive and angiogenic properties in human urothelial carcinoma. In clinical observations, statin administration was associated with better survival rates of early-stage bladder cancer patients. Our results may provide guidance for improving therapeutic strategies for the treatment of urothelial carcinoma. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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17 pages, 2793 KiB

Open AccessArticle

YY1 Oligomerization Is Regulated by Its OPB Domain and Competes with Its Regulation of Oncoproteins

by Shiyao Qiao, Wenmeng Wang, Cheng Yi, Qingqing Xu, Wenfei Wang, Jinming Shi, Daniel B. Stovall, Dangdang Li and Guangchao Sui

Cancers 2022, 14(7), 1611; https://doi.org/10.3390/cancers14071611 - 22 Mar 2022

Cited by 4 | Viewed by 2578

Abstract

Yin Yang 1 (YY1) plays an oncogenic role through regulating the expression of various cancer-related genes and activating key oncoproteins. Previous research reported that YY1 protein formed dimers or oligomers without definite biological implications. In this study, we first demonstrated the oncoprotein binding [...] Read more.

Yin Yang 1 (YY1) plays an oncogenic role through regulating the expression of various cancer-related genes and activating key oncoproteins. Previous research reported that YY1 protein formed dimers or oligomers without definite biological implications. In this study, we first demonstrated the oncoprotein binding (OPB) and zinc finger (ZF) domains of YY1 as the regions involved in its intermolecular interactions. ZFs are well-known for protein dimerization, so we focused on the OPB domain. After mutating three hydrophobic residues in the OPB to alanines, we discovered that YY1(F219A) and YY1(3A), three residues simultaneously replaced by alanines, were defective of intermolecular interaction. Meanwhile, the OPB peptide could robustly facilitate YY1 protein oligomerization. When expressed in breast cancer cells with concurrent endogenous YY1 knockdown, YY1(F219A) and (3A) mutants showed better capacity than wt in promoting cell proliferation and migration, while their interactions with EZH2, AKT and MDM2 showed differential alterations, especially with improved EZH2 binding affinity. Our study revealed a crucial role of the OPB domain in facilitating YY1 oligomerization and suggested a mutually exclusive regulation between YY1-mediated enhancer formation and its activities in promoting oncoproteins. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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19 pages, 9376 KiB

Open AccessArticle

Identification of a Chemotherapeutic Lead Molecule for the Potential Disruption of the FAM72A-UNG2 Interaction to Interfere with Genome Stability, Centromere Formation, and Genome Editing

by Senthil Renganathan, Subrata Pramanik, Rajasekaran Ekambaram, Arne Kutzner, Pok-Son Kim and Klaus Heese

Cancers 2021, 13(22), 5870; https://doi.org/10.3390/cancers13225870 - 22 Nov 2021

Cited by 8 | Viewed by 2671

Abstract

Family with sequence similarity 72 A (FAM72A) is a pivotal mitosis-promoting factor that is highly expressed in various types of cancer. FAM72A interacts with the uracil-DNA glycosylase UNG2, the enzyme that prevents mutagenesis by eliminating uracil from DNA molecules through cleaving the N-glycosylic [...] Read more.

Family with sequence similarity 72 A (FAM72A) is a pivotal mitosis-promoting factor that is highly expressed in various types of cancer. FAM72A interacts with the uracil-DNA glycosylase UNG2, the enzyme that prevents mutagenesis by eliminating uracil from DNA molecules through cleaving the N-glycosylic bond and initiating the base excision repair pathway, thus maintaining genome integrity. In the present study, we determined a specific FAM72A-UNG2 heterodimer protein interaction using molecular docking and dynamics. In addition, through in silico screening, we identified withaferin B as a molecule that can specifically prevent the FAM72A-UNG2 interaction by blocking its cell signaling pathways. Our results provide an excellent basis for possible therapeutic approaches in the clinical treatment of cancer. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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10 pages, 245 KiB

Open AccessArticle

by Wing-Lok Chan, Horace Cheuk-Wai Choi, Patty Pui-Ying Ho, Johnny Kin-San Lau, Rosa Pui-Ying Tse, Joyce Au, Vivian Lam, Ronald Liu, Isaac Ho, Charlotte Wong, Ben Cheung, Eric Lam, Daryn Chow, Ka-On Lam, Kwok-Keung Yuen and Dora Lai-Wan Kwong

Cancers 2021, 13(15), 3797; https://doi.org/10.3390/cancers13153797 - 28 Jul 2021

Cited by 4 | Viewed by 1883

Abstract

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 [...] Read more.

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a university hospital in Hong Kong. Patients were reviewed up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) were included. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo + ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted + ICI). A significantly higher proportion of patients using targeted + ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (≥65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. This large, real-world cohort demonstrates that targeted + ICI has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is essential in older populations. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

20 pages, 5091 KiB

Open AccessArticle

Blockade of AMPK-Mediated cAMP–PKA–CREB/ATF1 Signaling Synergizes with Aspirin to Inhibit Hepatocellular Carcinoma

by Hongying Zhang, Songpeng Yang, Jiao Wang and Yangfu Jiang

Cancers 2021, 13(7), 1738; https://doi.org/10.3390/cancers13071738 - 06 Apr 2021

Cited by 21 | Viewed by 4658

Abstract

Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize [...] Read more.

Aspirin can prevent or inhibit inflammation-related cancers, such as colorectal cancer and hepatocellular carcinoma (HCC). However, the effectiveness of chemotherapy may be compromised by activating oncogenic pathways in cancer cells. Elucidation of such chemoresistance mechanisms is crucial to developing novel strategies to maximize the anti-cancer effects of aspirin. Here, we report that aspirin markedly induces CREB/ATF1 phosphorylation in HCC cells, which compromises aspirin’s anti-HCC effect. Inhibition of AMP-activated protein kinase (AMPK) abrogates the induction of CREB/ATF1 phosphorylation by aspirin. Mechanistically, activation of AMPK by aspirin results in decreased expression of the urea cycle enzyme carbamoyl-phosphate synthase 1 (CPS1) in HCC cells and xenografts. Treatment with aspirin or CPS1 knockdown stimulates soluble adenylyl cyclase expression, thereby increasing cyclic AMP (cAMP) synthesis and stimulating PKA–CREB/ATF1 signaling. Importantly, abrogation of aspirin-induced CREB/ATF1 phosphorylation could sensitize HCC to aspirin. The bis-benzylisoquinoline alkaloid berbamine suppresses the expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), leading to protein phosphatase 2A-mediated downregulation of CREB/ATF1 phosphorylation. The combination of berbamine and aspirin significantly inhibits HCC in vitro and in vivo. These data demonstrate that the regulation of cAMP-PKA-CREB/ATF1 signaling represents a noncanonical function of CPS1. Targeting the PKA–CREB/ATF1 axis may be a strategy to improve the therapeutic effects of aspirin on HCC. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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Review

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12 pages, 1727 KiB

Open AccessReview

TrkA Co-Receptors: The Janus Face of TrkA?

by Sarah Trouvilliez, Chann Lagadec and Robert-Alain Toillon

Cancers 2023, 15(7), 1943; https://doi.org/10.3390/cancers15071943 - 23 Mar 2023

Cited by 2 | Viewed by 1927

Abstract

Larotrectinib and Entrectinib are specific pan-Trk tyrosine kinase inhibitors (TKIs) approved by the Food and Drug Administration (FDA) in 2018 for cancers with an NTRK fusion. Despite initial enthusiasm for these compounds, the French agency (HAS) recently reported their lack of efficacy. In [...] Read more.

Larotrectinib and Entrectinib are specific pan-Trk tyrosine kinase inhibitors (TKIs) approved by the Food and Drug Administration (FDA) in 2018 for cancers with an NTRK fusion. Despite initial enthusiasm for these compounds, the French agency (HAS) recently reported their lack of efficacy. In addition, primary and secondary resistance to these TKIs has been observed in the absence of other mutations in cancers with an NTRK fusion. Furthermore, when TrkA is overexpressed, it promotes ligand-independent activation, bypassing the TKI. All of these clinical and experimental observations show that genetics does not explain all therapeutic failures. It is therefore necessary to explore new hypotheses to explain these failures. This review summarizes the current status of therapeutic strategies with TrkA inhibitors, focusing on the mechanisms potentially involved in these failures and more specifically on the role of TrkA. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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26 pages, 2153 KiB

Open AccessReview

Regulation of Death Receptor Signaling by S-Palmitoylation and Detergent-Resistant Membrane Micro Domains—Greasing the Gears of Extrinsic Cell Death Induction, Survival, and Inflammation

by Jürgen Fritsch, Vinzenz Särchen and Wulf Schneider-Brachert

Cancers 2021, 13(11), 2513; https://doi.org/10.3390/cancers13112513 - 21 May 2021

Cited by 8 | Viewed by 3066

Abstract

Death-receptor-mediated signaling results in either cell death or survival. Such opposite signaling cascades emanate from receptor-associated signaling complexes, which are often formed in different subcellular locations. The proteins involved are frequently post-translationally modified (PTM) by ubiquitination, phosphorylation, or glycosylation to allow proper spatio-temporal [...] Read more.

Death-receptor-mediated signaling results in either cell death or survival. Such opposite signaling cascades emanate from receptor-associated signaling complexes, which are often formed in different subcellular locations. The proteins involved are frequently post-translationally modified (PTM) by ubiquitination, phosphorylation, or glycosylation to allow proper spatio-temporal regulation/recruitment of these signaling complexes in a defined cellular compartment. During the last couple of years, increasing attention has been paid to the reversible cysteine-centered PTM S-palmitoylation. This PTM regulates the hydrophobicity of soluble and membrane proteins and modulates protein:protein interaction and their interaction with distinct membrane micro-domains (i.e., lipid rafts). We conclude with which functional and mechanistic roles for S-palmitoylation as well as different forms of membrane micro-domains in death-receptor-mediated signal transduction were unraveled in the last two decades. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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30 pages, 5399 KiB

Open AccessReview

Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy

by Preeti Gupta, Aaliya Taiyab, Afzal Hussain, Mohamed F. Alajmi, Asimul Islam and Md. Imtaiyaz Hassan

Cancers 2021, 13(8), 1898; https://doi.org/10.3390/cancers13081898 - 15 Apr 2021

Cited by 34 | Viewed by 5256

Abstract

Sphingolipid metabolites have emerged as critical players in the regulation of various physiological processes. Ceramide and sphingosine induce cell growth arrest and apoptosis, whereas sphingosine-1-phosphate (S1P) promotes cell proliferation and survival. Here, we present an overview of sphingolipid metabolism and the compartmentalization of [...] Read more.

Sphingolipid metabolites have emerged as critical players in the regulation of various physiological processes. Ceramide and sphingosine induce cell growth arrest and apoptosis, whereas sphingosine-1-phosphate (S1P) promotes cell proliferation and survival. Here, we present an overview of sphingolipid metabolism and the compartmentalization of various sphingolipid metabolites. In addition, the sphingolipid rheostat, a fine metabolic balance between ceramide and S1P, is discussed. Sphingosine kinase (SphK) catalyzes the synthesis of S1P from sphingosine and modulates several cellular processes and is found to be essentially involved in various pathophysiological conditions. The regulation and biological functions of SphK isoforms are discussed. The functions of S1P, along with its receptors, are further highlighted. The up-regulation of SphK is observed in various cancer types and is also linked to radio- and chemoresistance and poor prognosis in cancer patients. Implications of the SphK/S1P signaling axis in human pathologies and its inhibition are discussed in detail. Overall, this review highlights current findings on the SphK/S1P signaling axis from multiple angles, including their functional role, mechanism of activation, involvement in various human malignancies, and inhibitor molecules that may be used in cancer therapy. Full article

(This article belongs to the Special Issue Targeting Signal Transduction Pathways in Cancer)

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