scholarly journals The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star

2020 ◽  
Vol 12 ◽  
pp. 175883592094094 ◽  
Author(s):  
Ruizhe Zhu ◽  
Gang Yang ◽  
Zhe Cao ◽  
Kexin Shen ◽  
Lianfang Zheng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Colorectal ◽  
Mammalian Target Of Rapamycin ◽  
Therapeutic Resistance ◽  
Preclinical Studies ◽  
Mtor Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase

Serum and glucocorticoid-inducible kinase 1 (SGK1) is an AGC kinase that has been reported to be involved in a variety of physiological and pathological processes. Recent evidence has accumulated that SGK1 acts as an essential Akt-independent mediator of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway in cancer. SGK1 is overexpressed in several tumors, including prostate cancer, colorectal carcinoma, glioblastoma, breast cancer, and endometrial cancer. The functions of SGK1 include regulating tumor growth, survival, metastasis, autophagy, immunoregulation, calcium (Ca2+) signaling, cancer stem cells, cell cycle, and therapeutic resistance. In this review, we introduce the pleiotropic role of SGK1 in the development and progression of tumors, summarize its downstream targets, and integrate the knowledge provided by preclinical studies that the prospect of SGK1 inhibition as a potential therapeutic approach.

scholarly journals FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K–Akt–mTOR signaling pathway

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Han Dai ◽  
Wenjing Hu ◽  
Lianying Zhang ◽  
Feiyu Jiang ◽  
Xiongmin Mao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Fibroblast Growth Factor 21 ◽  
Mtor Signaling Pathway ◽  
Lncap Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Glucose And Lipid Metabolism ◽  
Novel Target ◽  
Fgf21 Expression

AbstractFibroblast growth factor 21 (FGF21) plays an important role in regulating glucose and lipid metabolism, but its role in cancer is less well-studied. We aimed to investigate the action of FGF21 in the development of prostate cancer (PCa). Herein, we found that FGF21 expression was markedly downregulated in PCa tissues and cell lines. FGF21 inhibited the proliferation and clone formation of LNCaP cells (a PCa cell line) and promoted apoptosis. FGF21 also inhibited PCa cell migration and invasiveness. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that FGF21 was related to autophagy and the phosphatidylinositol 3-kinase–Akt kinase–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. Mechanistically, FGF21 promoted autophagy in LNCaP cells by inhibiting the PI3K–Akt–mTOR–70S6K pathway. In addition, FGF21 inhibited PCa tumorigenesis in vivo in nude mice. Altogether, our findings show that FGF21 inhibits PCa cell proliferation and promoted apoptosis in PCa cells through facilitated autophagy. Therefore, FGF21 might be a potential novel target in PCa therapy.

scholarly journals Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer

2013 ◽  
Vol 20 (3) ◽  
pp. R83-R99 ◽  
Author(s):  
Rhonda L Bitting ◽  
Andrew J Armstrong
Keyword(s):  
Prostate Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Castration Resistant Prostate Cancer ◽  
Phosphatidylinositol 3 Kinase ◽  
Resistance To Therapy ◽  
Castration Resistant ◽  
High Prevalence ◽  
Potential Use

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that has been linked to both tumorigenesis and resistance to therapy in prostate cancer and other solid tumors. Given the significance of the PI3K/Akt/mTOR pathway in integrating cell survival signals and the high prevalence of activating PI3K/Akt/mTOR pathway alterations in prostate cancer, inhibitors of this pathway have great potential for clinical benefit. Here, we review the role of the PI3K/Akt/mTOR pathway in prostate cancer and discuss the potential use of pathway inhibitors as single agents or in combination in the evolving treatment landscape of castration-resistant prostate cancer.

Biological Role of CDK 11 and 12 in Cell Cycle and its Function in Tumorigenesis

2020 ◽  
Author(s):  
Shamim Mushtaq
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Web Of Science ◽  
The Body ◽  
Main Role ◽  
Hallmarks Of Cancer ◽  
Cyclin Dependent Kinases ◽  
Tumor Studies ◽  
Cycle Regulation

Uninhibited proliferation and abnormal cell cycle regulation are the hallmarks of cancer. The main role of cyclin dependent kinases is to regulate the cell cycle and cell proliferation. These protein kinases are frequently down regulated or up regulated in various cancers. Two CDK family members, CDK 11 and 12, have contradicting views about their roles in different cancers. For example, one study suggests that the CDK 11 isoforms, p58, inhibits growth of breast cancer whereas, the CDK 11 isoform, p110, is highly expressed in breast tumor. Studies regarding CDK 12 show variation of opinion towards different parts of the body, however there is a consensus that upregulation of cdk12 increases the risk of breast cancer. Hence, CDK 11 and CDK 12 need to be analyzed to confirm their mechanism and their role regarding therapeutics, prognostic value, and ethnicity in cancer. This article gives an outline on both CDKs of information known up to date from Medline, PubMed, Google Scholar and Web of Science search engines, which were explored and thirty relevant researches were finalized.

scholarly journals Matrix degradation and cell proliferation are coupled to promote invasion and escape from an engineered human breast microtumor

2021 ◽  
Vol 13 (1) ◽  
pp. 17-29
Author(s):  
Emann M Rabie ◽  
Sherry X Zhang ◽  
Andreas P Kourouklis ◽  
A Nihan Kilinc ◽  
Allison K Simi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Type I ◽  
Matrix Degradation ◽  
Human Breast ◽  
Rate Of Invasion

Abstract Metastasis, the leading cause of mortality in cancer patients, depends upon the ability of cancer cells to invade into the extracellular matrix that surrounds the primary tumor and to escape into the vasculature. To investigate the features of the microenvironment that regulate invasion and escape, we generated solid microtumors of MDA-MB-231 human breast carcinoma cells within gels of type I collagen. The microtumors were formed at defined distances adjacent to an empty cavity, which served as an artificial vessel into which the constituent tumor cells could escape. To define the relative contributions of matrix degradation and cell proliferation on invasion and escape, we used pharmacological approaches to block the activity of matrix metalloproteinases (MMPs) or to arrest the cell cycle. We found that blocking MMP activity prevents both invasion and escape of the breast cancer cells. Surprisingly, blocking proliferation increases the rate of invasion but has no effect on that of escape. We found that arresting the cell cycle increases the expression of MMPs, consistent with the increased rate of invasion. To gain additional insight into the role of cell proliferation in the invasion process, we generated microtumors from cells that express the fluorescent ubiquitination-based cell cycle indicator. We found that the cells that initiate invasions are preferentially quiescent, whereas cell proliferation is associated with the extension of invasions. These data suggest that matrix degradation and cell proliferation are coupled during the invasion and escape of human breast cancer cells and highlight the critical role of matrix proteolysis in governing tumor phenotype.

scholarly journals Inhibition of Prostate Cancer DU-145 Cells Proliferation by Anthopleura anjunae Oligopeptide (YVPGP) via PI3K/AKT/mTOR Signaling Pathway

Marine Drugs ◽  
2018 ◽  
Vol 16 (9) ◽  
pp. 325 ◽  
Author(s):  
Xiaojuan Li ◽  
Yunping Tang ◽  
Fangmiao Yu ◽  
Yu Sun ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Nude Mouse Model ◽  
Dose Dependent

We investigated the antitumor mechanism of Anthopleura anjunae oligopeptide (AAP-H, YVPGP) in prostate cancer DU-145 cells in vitro and in vivo. Results indicated that AAP-H was nontoxic and exhibited antitumor activities. Cell cycle analysis indicated that AAP-H may arrest DU-145 cells in the S phase. The role of the phosphatidylinositol 3-kinase/protein kinase B/mammalian rapamycin target protein (PI3K/AKT/mTOR) signaling pathway in the antitumor mechanism of APP-H was investigated. Results showed that AAP-H treatment led to dose-dependent reduction in the levels of p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448), whereas t-AKT and t-PI3K levels remained unaltered compared to the untreated DU-145 cells. Inhibition of PI3K/AKT/mTOR signaling pathway in the DU-145 cells by employing inhibitor LY294002 (10 μM) or rapamycin (20 nM) effectively attenuated AAP-H-induced phosphorylation of AKT and mTOR. At the same time, inhibitor addition further elevated AAP-H-induced cleaved-caspase-3 levels. Furthermore, the effect of AAP-H on tumor growth and the role of the PI3K/AKT/mTOR signaling pathway in nude mouse model were also investigated. Immunohistochemical analysis showed that activated AKT, PI3K, and mTOR levels were reduced in DU-145 xenografts. Western blotting showed that AAP-H treatment resulted in dose-dependent reduction in p-AKT (Ser473), p-PI3K (p85), and p-mTOR (Ser2448) levels, whereas t-AKT and t-PI3K levels remained unaltered. Similarly, Bcl-xL levels decreased, whereas that of Bax increased after AAP-H treatment. AAP-H also increased initiator (caspase 8 and 9) and executor caspase (caspase 3 and 7) levels. Therefore, the antitumor mechanism of APP-H on DU-145 cells may involve regulation of the PI3K/AKT/mTOR signaling pathway, which eventually promotes apoptosis via mitochondrial and death receptor pathways. Thus, the hydrophobic oligopeptide (YVPGP) can be developed as an adjuvant for the prevention or treatment of prostate cancer in the future.

scholarly journals A Review on the Carcinogenic Roles of DSCAM-AS1

2021 ◽  
Vol 9 ◽  
Author(s):  
Soudeh Ghafouri-Fard ◽  
Tayyebeh Khoshbakht ◽  
Mohammad Taheri ◽  
Kaveh Ebrahimzadeh
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Antisense Rna ◽  
Breast Tumor ◽  
Cancer Colorectal ◽  
Small Cell ◽  
Small Cell Lung ◽  
Breast Tumor Cells ◽  
Non Coding Rnas

Long non-coding RNAs (lncRNAs) are a group of transcripts with fundamental roles in the carcinogenesis. DSCAM Antisense RNA 1 (DSCAM−AS1) is an example of this group of transcripts which has been firstly identified in an attempt to find differentially expressed transcripts between breast tumor cells and benign breast samples. The pathogenic roles of DSCAM-AS1 have been vastly assessed in breast cancer, yet its roles are not restricted to this type of cancer. Independent studies in non-small cell lung cancer, colorectal cancer, osteosarcoma, hepatocellular carcinoma, melanoma and cervical cancer have validated participation of DSCAM-AS1 in the carcinogenic processes. miR-577, miR-122-5p, miR-204-5p, miR-136, miR−137, miR−382, miR−183, miR−99, miR-3173-5p, miR-874-3p, miR-874-3p, miR-150-5p, miR-2467-3p, miR-216b, miR-384, miR-186-5p, miR-338-3p, miR-877-5p and miR-101 are among miRNAs which interact with DSCAM-AS1. Moreover, this lncRNA has interactions with Wnt/β-catenin pathway. The current study aims at summarization of the results of studies which focused on the assessment of oncogenic role of DSCAM-AS1.

scholarly journals The Potential Prognostic Role of Oligosaccharide-Binding Fold-Containing Protein 2A (OBFC2A) in Triple-Negative Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Qianxue Wu ◽  
Xin Tang ◽  
Wenming Zhu ◽  
Qing Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Candidate Genes ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
G1 Phase ◽  
And Migration

BackgroundPatients with triple-negative breast cancer (TNBC) have poor overall survival. The present study aimed to investigate the potential prognostics of TNBC by analyzing breast cancer proteomic and transcriptomic datasets.MethodsCandidate proteins selected from CPTAC (the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium) were validated using datasets from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium). Kaplan-Meier analysis and ROC (receiver operating characteristic) curve analysis were performed to explore the prognosis of candidate genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis were performed on the suspected candidate genes. Single-cell RNA-seq (scRNA-seq) data from GSE118389 were used to analyze the cell clusters in which OBFC2A (Oligosaccharide-Binding Fold-Containing Protein 2A) was mainly distributed. TIMER (Tumor Immune Estimation Resource) was used to verify the correlation between OBFC2A expression and immune infiltration. Clone formation assays and wound healing assays were used to detect the role of OBFC2A expression on the proliferation, invasion, and migration of breast cancer cells. Flow cytometry was used to analyze the effects of silencing OBFC2A on breast cancer cell cycle and apoptosis.ResultsSix candidate proteins were found to be differentially expressed in non-TNBC and TNBC groups from CPTAC. However, only OBFC2A was identified as an independently poor prognostic gene marker in METABRIC (HR=3.658, 1.881-7.114). And OBFC2A was associated with immune functions in breast cancer. Biological functional experiments showed that OBFC2A might promote the proliferation and migration of breast cancer cells. The inhibition of OBFC2A expression blocked the cell cycle in G1 phase and inhibited the transformation from G1 phase to S phase. Finally, downregulation of OBFC2A also increased the total apoptosis rate of cells.ConclusionOn this basis, OBFC2A may be a potential prognostic biomarker for TNBC.

CYCLONE 1: A phase 2 study of abemaciclib in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a novel hormonal agent and taxane-based chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5086-TPS5086
Author(s):  
Neeraj Agarwal ◽  
Stephane Oudard ◽  
Josep M. Piulats ◽  
Michael Thomas Schweizer ◽  
Aude Flechon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Radiographic Progression ◽  
Prostate Cancer Cell ◽  
Response Rate ◽  
Single Agent ◽  
Phase 2 ◽  
Phase 2 Study

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 & 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 & 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 & 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material <12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.

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