A dual-targeted molecular therapy of PP242 and cetuximab plays an anti-tumor effect through EGFR downstream signaling pathways in colorectal cancer

Hematopoiesis, the process by which the hematopoietic stem cells and progenitors differentiate into blood cells of various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Despite the many controls that regulate hematopoiesis, mutations in the regulatory genes capable of promoting leukemogenesis may occur. The <em>FLT3</em> gene encodes a tyrosine kinase receptor that plays a key role in controlling survival, proliferation and differentiation of hematopoietic cells. Mutations in this gene are critical in causing a deregulation of the delicate balance between cell proliferation and differentiation. In this review, we provide an update on the structure, synthesis and activation of the FLT3 receptor and the subsequent activation of multiple downstream signaling pathways. We also review activating FLT3 mutations that are frequently identified in acute myeloid leukemia, cause activation of more complex downstream signaling pathways and promote leukemogenesis. Finally, FLT3 has emerged as an important target for molecular therapy. We, therefore, report on some recent therapies directed against it.

Download Full-text

Chemotherapy and Targeted Molecular Therapy in Patients with Metastatic Colorectal Cancer

Nippon Daicho Komonbyo Gakkai Zasshi ◽

10.3862/jcoloproctology.67.897 ◽

2014 ◽

Vol 67 (10) ◽

pp. 897-905

Author(s):

Hideyuki Mishima ◽

Kengo Kimura ◽

Masakazu Ikenaga ◽

Masayoshi Yasui ◽

Tairin Uchino ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Molecular Therapy ◽

Targeted Molecular Therapy

Download Full-text

Down-Regulation of Cannabinoid Type 1 (CB1) Receptor and its Downstream Signaling Pathways in Metastatic Colorectal Cancer

Cancers ◽

10.3390/cancers11050708 ◽

2019 ◽

Vol 11 (5) ◽

pp. 708 ◽

Cited By ~ 2

Author(s):

Valeria Tutino ◽

Maria Gabriella Caruso ◽

Valentina De Nunzio ◽

Dionigi Lorusso ◽

Nicola Veronese ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathways ◽

Normal Mucosa ◽

Cb1 Receptor ◽

Receptor Expression ◽

Altered Expression ◽

Downstream Signaling ◽

Metastatic Process

Changes in the regulation of endocannabinoid production, together with an altered expression of their receptors are hallmarks of cancer, including colorectal cancer (CRC). Although several studies have been conducted to understand the biological role of the CB1 receptor in cancer, little is known about its involvement in the metastatic process of CRC. The aim of this study was to investigate the possible link between CB1 receptor expression and the presence of metastasis in patients with CRC, investigating the main signaling pathways elicited downstream of CB1 receptor in colon cancer. Fifty-nine consecutive patients, with histologically proven colorectal cancer, were enrolled in the study, of which 30 patients with synchronous metastasis, at first diagnosis and 29 without metastasis. A low expression of CB1 receptor were detected in primary tumor tissue of CRC patients with metastasis and consequently, we observed an alteration of CB1 receptor downstream signaling. These signaling routes were also altered in intestinal normal mucosa, suggesting that, normal mucosa surrounding the tumor provides a realistic picture of the molecules involved in tissue malignant transformation. These observations contribute to the idea that drugs able to induce CB1 receptor expression can be helpful in order to set new anticancer therapeutic strategies.

Download Full-text

The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.768861 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kha Wai Hon ◽

Syafiq Asnawi Zainal Abidin ◽

Iekhsan Othman ◽

Rakesh Naidu

Keyword(s):

Colorectal Cancer ◽

Signaling Pathways ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Kinase Inhibitors ◽

Protein Kinase Inhibitors ◽

Metabolic Reprogramming ◽

Metabolic Inhibitors ◽

Downstream Signaling ◽

Insight Into

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.

Download Full-text

Author response for "The role of Long Non‐Coding RNAs ( lncRNAs ) and downstream signaling pathways in Leukemia progression"

10.1002/hon.2776/v2/response1 ◽

2020 ◽

Author(s):

Yadong Liu ◽

Penghao Sun ◽

Yuhao Zhao ◽

Bin Liu

Keyword(s):

Signaling Pathways ◽

Author Response ◽

Downstream Signaling ◽

Non Coding Rnas

Download Full-text

LMNB2 promotes the progression of colorectal cancer by silencing p21 expression

Cell Death and Disease ◽

10.1038/s41419-021-03602-1 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Chen-Hua Dong ◽

Tao Jiang ◽

Hang Yin ◽

Hu Song ◽

Yi Zhang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Progression ◽

Molecular Mechanisms ◽

Gene Set Enrichment Analysis ◽

Molecular Therapy ◽

Cycle Progression ◽

Cancer Tissues

AbstractColorectal cancer is the second common cause of death worldwide. Lamin B2 (LMNB2) is involved in chromatin remodeling and the rupture and reorganization of nuclear membrane during mitosis, which is necessary for eukaryotic cell proliferation. However, the role of LMNB2 in colorectal cancer (CRC) is poorly understood. This study explored the biological functions of LMNB2 in the progression of colorectal cancer and explored the possible molecular mechanisms. We found that LMNB2 was significantly upregulated in primary colorectal cancer tissues and cell lines, compared with paired non-cancerous tissues and normal colorectal epithelium. The high expression of LMNB2 in colorectal cancer tissues is significantly related to the clinicopathological characteristics of the patients and the shorter overall and disease-free cumulative survival. Functional analysis, including CCK8 cell proliferation test, EdU proliferation test, colony formation analysis, nude mouse xenograft, cell cycle, and apoptosis analysis showed that LMNB2 significantly promotes cell proliferation by promoting cell cycle progression in vivo and in vitro. In addition, gene set enrichment analysis, luciferase report analysis, and CHIP analysis showed that LMNB2 promotes cell proliferation by regulating the p21 promoter, whereas LMNB2 has no effect on cell apoptosis. In summary, these findings not only indicate that LMNB2 promotes the proliferation of colorectal cancer by regulating p21-mediated cell cycle progression, but also suggest the potential value of LMNB2 as a clinical prognostic marker and molecular therapy target.

Download Full-text

Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

Cell Communication and Signaling ◽

10.1186/s12964-021-00712-3 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Camille Ternet ◽

Christina Kiel

Keyword(s):

Colorectal Cancer ◽

Signaling Pathways ◽

Intestinal Microbiota ◽

Critical Role ◽

Neuroendocrine Cells ◽

Cell Junction ◽

Intestinal Cell ◽

Intestinal Homeostasis ◽

Cell Functions ◽

The Impact

AbstractThe intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.

Download Full-text

MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

Cells ◽

10.3390/cells10010039 ◽

2020 ◽

Vol 10 (1) ◽

pp. 39

Author(s):

Crescenzo Massaro ◽

Elham Safadeh ◽

Giulia Sgueglia ◽

Hendrik G. Stunnenberg ◽

Lucia Altucci ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Signaling Pathways ◽

Cancer Progression ◽

Therapy Resistance ◽

Disease Recurrence ◽

Hormone Signaling ◽

Cancer Resistance ◽

Comprehensive Overview ◽

Substantial Progress

Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.

Download Full-text

Immunoregulatory Property of C-Type Lectin-Like Receptors in Fibrosing Interstitial Lung Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21103665 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3665

Author(s):

Wiwin Is Effendi ◽

Tatsuya Nagano ◽

Helmia Hasan ◽

Resti Yudhawati

Keyword(s):

Immune System ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Lung Diseases ◽

Wound Repair ◽

Tissue Injury ◽

Interstitial Lung Diseases ◽

Downstream Signaling ◽

Cytokine Activation ◽

Immune Impairment

The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD.

Download Full-text