The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.

Download Full-text

The Role of Extracellular Vesicles in the Development of a Cancer Stem Cell Microenvironment Niche and Potential Therapeutic Targets

Cancers ◽

10.3390/cancers13102435 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2435

Author(s):

Thomas J. Brown ◽

Victoria James

Keyword(s):

Systematic Review ◽

Tumor Microenvironment ◽

Extracellular Vesicles ◽

Multiple Cancer ◽

Therapeutic Targeting ◽

Small Component ◽

Facilitated Communication ◽

Cell Microenvironment ◽

Cancer Types

Cancer stem cells (CSCs) have increasingly been shown to be a crucial element of heterogenous tumors. Although a relatively small component of the population, they increase the resistance to treatment and the likelihood of recurrence. In recent years, it has been shown, across multiple cancer types (e.g., colorectal, breast and prostate), that reciprocal communication between cancer and the microenvironment exists, which is, in part, facilitated by extracellular vesicles (EVs). However, the mechanisms of this method of communication and its influence on CSC populations is less well-understood. Therefore, the aim of this systematic review is to determine the evidence that supports the role of EVs in the manipulation of the tumor microenvironment to promote the survival of CSCs. Embase and PubMed were used to identify all studies on the topic, which were screened using PRISMA guidelines, resulting in the inclusion of 16 studies. These 16 studies reported on the EV content, pathways altered by EVs and therapeutic targeting of CSC through EV-mediated changes to the microenvironment. In conclusion, these studies demonstrated the role of EV-facilitated communication in maintaining CSCs via manipulation of the tumor microenvironment, demonstrating the potential of creating therapeutics to target CSCs. However, further works are needed to fully understand the targetable mechanisms upon which future therapeutics can be based.

Download Full-text

Involvement of CD24 in Multiple Cancer Related Pathways Makes It an Interesting New Target for Cancer Therapy

Current Cancer Drug Targets ◽

10.2174/1570163814666170818125036 ◽

2018 ◽

Vol 18 (4) ◽

pp. 328-336 ◽

Cited By ~ 12

Author(s):

Shirin Eyvazi ◽

Bahram Kazemi ◽

Siavoush Dastmalchi ◽

Mojgan Bandehpour

Keyword(s):

Cancer Cells ◽

Signaling Pathways ◽

Src Kinases ◽

Invasion And Metastasis ◽

Multiple Cancer ◽

Exact Role ◽

Promote Cell Proliferation ◽

Downstream Effectors ◽

Cluster Of Differentiation

CD24 (cluster of differentiation 24) is a small heavy glycosylated protein, which is overexpressed in many cancer and some cancer stem cells and is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in these processes is not fully understood, however, in this article, it has been tried to present a collection of cancer-related mechanisms attributed to CD24. Based on the literature, CD24 dis-regulates different signaling pathways in various cancer cells, including; Src kinases, STAT3, EGFR, Wnt/β-catenin and MAPK. Src kinases play an important role in the signaling pathways which activate p38 MAPK and STAT3 pathways. Akt and ERK are downstream effectors of CD24-activated EGFR, which promote cell proliferation, invasion and metastasis. CD24 increases the expression of HER2 by the activation of NF-κB transcription factor. Moreover, CD24 up-regulates the expression of miR-21 oncomir through the activation of Src kinases. Identification of the details of these pathways and also new pathways will help researchers to explore new CD24 targeted therapies.

Download Full-text

Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21238991 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8991

Author(s):

Jingwen Xu ◽

Nipa H. Patel ◽

David A. Gewirtz

Keyword(s):

Drug Resistance ◽

Clinical Studies ◽

Chemotherapy Resistance ◽

Clinical Trial Design ◽

Cellular Survival ◽

Treatment Regimens ◽

Response To Chemotherapy ◽

Cancer Types ◽

Triangular Relationship

Chemotherapy and radiation often induce a number of cellular responses, such as apoptosis, autophagy, and senescence. One of the major regulators of these processes is p53, an essential tumor suppressor that is often mutated or lost in many cancer types and implicated in early tumorigenesis. Gain of function (GOF) p53 mutations have been implicated in increased susceptibility to drug resistance, by compromising wildtype anti-tumor functions of p53 or modulating key p53 processes that confer chemotherapy resistance, such as autophagy. Autophagy, a cellular survival mechanism, is initially induced in response to chemotherapy and radiotherapy, and its cytoprotective nature became the spearhead of a number of clinical trials aimed to sensitize patients to chemotherapy. However, increased pre-clinical studies have exemplified the multifunctional role of autophagy. Additionally, compartmental localization of p53 can modulate induction or inhibition of autophagy and may play a role in autophagic function. The duality in p53 function and its effects on autophagic function are generally not considered in clinical trial design or clinical therapeutics; however, ample pre-clinical studies suggest they play a role in tumor responses to therapy and drug resistance. Further inquiry into the interconnection between autophagy and p53, and its effects on chemotherapeutic responses may provide beneficial insights on multidrug resistance and novel treatment regimens for chemosensitization.

Download Full-text

SALL4 and microRNA: The Role of Let-7

Genes ◽

10.3390/genes12091301 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1301

Author(s):

Jun Liu ◽

Madeline A. Sauer ◽

Shaza Hussein ◽

Junyu Yang ◽

Daniel G. Tenen ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem ◽

Mammalian Development ◽

Multiple Cancer ◽

Self Renewal ◽

Zinc Finger Transcription Factor ◽

Different Types ◽

Organ Specific ◽

Cancer Types

SALL4 is a zinc finger transcription factor that belongs to the spalt-like (SALL) gene fam-ily. It plays important roles in the maintenance of self-renewal and pluripotency of embryonic stem cells, and its expression is repressed in most adult organs. SALL4 re-expression has been observed in different types of human cancers, and dysregulation of SALL4 contributes to the pathogenesis, metastasis, and even drug resistance of multiple cancer types. Surprisingly, little is known regard-ing how SALL4 expression is controlled, but recently microRNAs (miRNAs) have emerged as im-portant regulators of SALL4. Due to the ability of regulating targets differentially in specific tissues, and recent advances in systemic and organ specific miRNA delivery mechanisms, miRNAs have emerged as promising therapeutic targets for cancer treatment. In this review, we summarize cur-rent knowledge of the interaction between SALL4 and miRNAs in mammalian development and cancer, paying particular attention to the emerging roles of the Let-7/Lin28 axis. In addition, we discuss the therapeutic prospects of targeting SALL4 using miRNA-based strategies, with a focus on the Let-7/LIN28 axis.

Download Full-text

Molecular characterization and clinical relevance of m6A regulators across 33 cancer types

Molecular Cancer ◽

10.1186/s12943-019-1066-3 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 40

Author(s):

Yongsheng Li ◽

Jun Xiao ◽

Jing Bai ◽

Yi Tian ◽

Yinwei Qu ◽

...

Keyword(s):

Clinical Relevance ◽

Critical Role ◽

Genetic Alterations ◽

Biological Processes ◽

Valuable Resource ◽

Multiple Cancer ◽

Molecular Alterations ◽

Prognostic Stratification ◽

Cancer Types

Abstract The methylation of N6 adenosine (m6A) plays a critical role in diverse biological processes. However, knowledge regarding the reconstitution of m6A across cancer types is still lacking. Here, we systematically analyzed the molecular alterations and clinical relevance of m6A regulators across > 10,000 subjects representing 33 cancer types. We found that there are widespread genetic alterations to m6A regulators, and that their expression levels are significantly correlated with the activity of cancer hallmark-related pathways. Moreover, m6A regulators were found to be potentially useful for prognostic stratification, and we identified IGF2BP3 as a potential oncogene across multiple cancer types. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of m6A regulators in cancer.

Download Full-text

The Therapeutic Potential of miR-7 in Cancers

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190904141922 ◽

2019 ◽

Vol 19 (20) ◽

pp. 1707-1716 ◽

Cited By ~ 3

Author(s):

Miao Li ◽

Meng Pan ◽

Chengzhong You ◽

Jun Dou

Keyword(s):

Tumor Suppressor ◽

Future Study ◽

Therapeutic Potential ◽

Biological Processes ◽

Multiple Cancer ◽

Current Review ◽

Cancer Types ◽

The Relationship ◽

Potent Tumor

MiRNAs play an important role in cancers. As a potent tumor suppressor, miRNA-7(miR-7) has been demonstrated to inhibit the diverse fundamental biological processes in multiple cancer types including initiation, growth and metastasis by targeting a number of molecules and signaling pathways. This current review summarizes and discusses the relationship between miR-7 and cancers and the therapeutic potential of miR-7 in cancers. It may provide new integrative understanding for future study on the role of miR-7 in cancers.

Download Full-text

Small ring has big potential: insights into extrachromosomal DNA in cancer

Cancer Cell International ◽

10.1186/s12935-021-01936-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yihao Wang ◽

Rui Huang ◽

Guopei Zheng ◽

Jianfeng Shen

Keyword(s):

Molecular Mechanisms ◽

Small Ring ◽

Extrachromosomal Dna ◽

Multiple Cancer ◽

Normal Tissues ◽

Oncogene Activation ◽

Technical Advances ◽

Cancer Types ◽

Underlying Mechanisms

AbstractRecent technical advances have led to the discovery of novel functions of extrachromosomal DNA (ecDNA) in multiple cancer types. Studies have revealed that cancer-associated ecDNA shows a unique circular shape and contains oncogenes that are more frequently amplified than that in linear chromatin DNA. Importantly, the ecDNA-mediated amplification of oncogenes was frequently found in most cancers but rare in normal tissues. Multiple reports have shown that ecDNA has a profound impact on oncogene activation, genomic instability, drug sensitivity, tumor heterogeneity and tumor immunology, therefore may offer the potential for cancer diagnosis and therapeutics. Nevertheless, the underlying mechanisms and future applications of ecDNA remain to be determined. In this review, we summarize the basic concepts, biological functions and molecular mechanisms of ecDNA. We also provide novel insights into the fundamental role of ecDNA in cancer.

Download Full-text

Insights Into the Function and Clinical Application of HDAC5 in Cancer Management

Frontiers in Oncology ◽

10.3389/fonc.2021.661620 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jun Yang ◽

Chaoju Gong ◽

Qinjian Ke ◽

Zejun Fang ◽

Xiaowen Chen ◽

...

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

Regulatory Mechanisms ◽

Biological Functions ◽

Multiple Cancer ◽

Aberrant Expression ◽

Cancer Management ◽

Cancer Types ◽

Proliferation And Invasion

Histone deacetylase 5 (HDAC5) is a class II HDAC. Aberrant expression of HDAC5 has been observed in multiple cancer types, and its functions in cell proliferation and invasion, the immune response, and maintenance of stemness have been widely studied. HDAC5 is considered as a reliable therapeutic target for anticancer drugs. In light of recent findings regarding the role of epigenetic reprogramming in tumorigenesis, in this review, we provide an overview of the expression, biological functions, regulatory mechanisms, and clinical significance of HDAC5 in cancer.

Download Full-text

Role of RUNX2 in Melanoma: A New Player in Tumor Progression and Resistance to Therapy

10.5772/intechopen.97105 ◽

2021 ◽

Author(s):

Rachael Pulica ◽

Cohen Solal Karine ◽

Ahmed Lasfar

Keyword(s):

Osteoblast Differentiation ◽

Skeletal Development ◽

Critical Role ◽

Invasion And Metastasis ◽

Braf Mutations ◽

Mesenchymal Progenitors ◽

Oncogenic Pathways ◽

Cancer Types ◽

Braf Mutant

RUNX2, a transcription factor, initially known for its indispensable role in skeletal development. RUNX2 is essential for osteoblast differentiation and the maintain of the osteocyte balance. RUNX2 acts directly on osteoblasts via Fgf pathway or on mesenchymal progenitors through Hedgehog, Wnt, Pthlh and DLX5. Currently, many reports point its critical role in the progression and metastasis of several cancer types. RUNX2 is involved in EMT process, invasion and metastasis through the modulation of important oncogenic pathways, including Wnt, FAK/PTK and AKT. In melanoma, RUNX2 is a key player in mediating intrinsic RTK-associated pro-oncogenic properties. We have showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL, in melanoma cells rendered resistant to BRAF mutant inhibitors. Approximately half of melanomas carry BRAF mutations which enhance tumor invasion and metastasis. In this chapter, we describe the potential mechanisms, leading to the upregulation of RUNX2 in melanoma with BRAF mutations. We also highlight the critical role of PI3K/AKT in the expression and activation of RUNX2, and its consequences on the regulation of many critical factors, controlling cancer invasion and metastasis.

Download Full-text

Aberrant Cholesterol Metabolism in Ovarian Cancer: Identification of Novel Therapeutic Targets

Frontiers in Oncology ◽

10.3389/fonc.2021.738177 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiangnan He ◽

Michelle K.Y. Siu ◽

Hextan Y. S. Ngan ◽

Karen K. L. Chan

Keyword(s):

Ovarian Cancer ◽

Mammalian Cells ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Therapeutic Targets ◽

Multiple Cancer ◽

Cancer Types ◽

Characteristic Features ◽

Rate Limiting

Cholesterol is an essential substance in mammalian cells, and cholesterol metabolism plays crucial roles in multiple biological functions. Dysregulated cholesterol metabolism is a metabolic hallmark in several cancers, beyond the Warburg effect. Reprogrammed cholesterol metabolism has been reported to enhance tumorigenesis, metastasis and chemoresistance in multiple cancer types, including ovarian cancer. Ovarian cancer is one of the most aggressive malignancies worldwide. Alterations in metabolic pathways are characteristic features of ovarian cancer; however, the specific role of cholesterol metabolism remains to be established. In this report, we provide an overview of the key proteins involved in cholesterol metabolism in ovarian cancer, including the rate-limiting enzymes in cholesterol biosynthesis, and the proteins involved in cholesterol uptake, storage and trafficking. Also, we review the roles of cholesterol and its derivatives in ovarian cancer and the tumor microenvironment, and discuss promising related therapeutic targets for ovarian cancer.

Download Full-text