scholarly journals Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei-Ching Chen ◽  
Minh D. To ◽  
Peter M. K. Westcott ◽  
Reyno Delrosario ◽  
Il-Jin Kim ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Er Stress ◽  
Cancer Therapeutics ◽  
Human Tumors ◽  
Differential Splicing ◽  
Pharmacological Inhibition ◽  
Coordinated Regulation ◽  
Clinical Drugs

AbstractThe commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics.

scholarly journals An Extract of Taro (Colocasia esculenta) Mediates Potent Inhibitory Actions on Metastatic and Cancer Stem Cells by Tumor Cell-Autonomous and Immune-Dependent Mechanisms

2021 ◽  
Vol 15 ◽  
pp. 117822342110349
Author(s):  
Namita Kundu ◽  
Xinrong Ma ◽  
Stephen Hoag ◽  
Fang Wang ◽  
Ahmed Ibrahim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Tumor Cell ◽  
Cell Lines ◽  
Nk Cell ◽  
Cancer Therapeutics ◽  
Colocasia Esculenta ◽  
Biologically Active ◽  
Tumor Cell Migration

The taro plant, Colocasia esculenta, contains bioactive proteins with potential as cancer therapeutics. Several groups have reported anti-cancer activity in vitro and in vivo of taro-derived extracts (TEs). We reported that TE inhibits metastasis in a syngeneic murine model of Triple-Negative Breast Cancer (TNBC). Purpose: We sought to confirm our earlier studies in additional models and to identify novel mechanisms by which efficacy is achieved. Methods: We employed a panel of murine and human breast and ovarian cancer cell lines to determine the effect of TE on tumor cell viability, migration, and the ability to support cancer stem cells. Two syngeneic models of TNBC were employed to confirm our earlier report that TE potently inhibits metastasis. Cancer stem cell assays were employed to determine the ability of TE to inhibit tumorsphere-forming ability and to inhibit aldehyde dehydrogenase activity. To determine if host immunity contributes to the mechanism of metastasis inhibition, efficacy was assessed in immune-compromised mice. Results: We demonstrate that viability of some, but not all cell lines is inhibited by TE. Likewise, tumor cell migration is inhibited by TE. Using 2 immune competent, syngeneic models of TNBC, we confirm our earlier findings that tumor metastasis is potently inhibited by TE. We also demonstrate, for the first time, that TE directly inhibits breast cancer stem cells. Administration of TE to mice elicits expansion of several spleen cell populations but it was not known if host immune cells contribute to the mechanism by which TE inhibits tumor cell dissemination. In novel findings, we now show that the ability of TE to inhibit metastasis relies on immune T-cell-dependent, but not B cell or Natural Killer (NK)-cell-dependent mechanisms. Thus, both tumor cell-autonomous and host immune factors contribute to the mechanisms underlying TE efficacy. Our long-term goal is to evaluate TE efficacy in clinical trials. Most of our past studies as well as many of the results reported in this report were carried out using an isolation protocol described earlier (TE). In preparation for a near future clinical trial, we have now developed a strategy to isolate an enriched taro fraction, TE-method 2, (TE-M2) as well as a more purified subfraction (TE-M2F1) which can be scaled up under Good Manufacturing Practice (GMP) conditions for evaluation in human subjects. We demonstrate that TE-M2 and TE-M2F1 retain the anti-metastatic properties of TE. Conclusions: These studies provide further support for the continued examination of biologically active components of Colocasia esculenta as potential new therapeutic entities and identify a method to isolate sufficient quantities under GMP conditions to conduct early phase clinical studies.

Cancer stem cells: the development of new cancer therapeutics

2011 ◽  
Vol 11 (7) ◽  
pp. 875-892 ◽  
Author(s):  
Roberto Scatena ◽  
Patrizia Bottoni ◽  
Alessandro Pontoglio ◽  
Bruno Giardina
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Therapeutics

scholarly journals Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics

2021 ◽  
Vol 22 (23) ◽  
pp. 13044
Author(s):  
Ari Meerson ◽  
Soliman Khatib ◽  
Jamal Mahajna
Keyword(s):  
Stem Cells ◽  
Natural Products ◽  
Cancer Stem Cells ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Cancer Therapeutics ◽  
Chemotherapeutic Agents ◽  
Biologically Active ◽  
Approved Drugs ◽  
Multiple Signaling

Cancer stem cells (CSC) have been identified in several types of solid tumors. In some cases, CSC may be the source of all the tumor cells, the cause of the tumor’s resistance to chemotherapeutic agents, and the source of metastatic cells. Thus, a combination therapy targeting non-CSC tumor cells as well as specifically targeting CSCs holds the potential to be highly effective. Natural products (NPs) have been a historically rich source of biologically active compounds and are known for their ability to influence multiple signaling pathways simultaneously with negligible side effects. In this review, we discuss the potential of NPs in targeting multiple signaling pathways in CSC and their potential to augment the efficacy of standard cancer therapy. Specifically, we focus on the anti-CSC activities of flavonoids, FDA-approved drugs originating from natural sources. Additionally, we emphasize the potential of NPs in targeting microRNA-mediated signaling, given the roles of microRNA in the maintenance of the CSC phenotype.

scholarly journals Sec23a Inhibits The Self-Renewal of Melanoma Cancer Stem Cells via Inactivation of ER-Phagy

2021 ◽  
Author(s):  
H.Rosie Xing ◽  
Zhiwei Sun ◽  
Doudou Liu ◽  
Bin Zeng ◽  
Qiting Zhao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Er Stress ◽  
Cell Line ◽  
Melanoma Cell ◽  
Melanoma Cell Line ◽  
Human Melanoma ◽  
The Self ◽  
Human Melanoma Cell ◽  
Self Renewal

Abstract Background The genesis and developments of solid tumors, analogous to the renewal of healthy tissues, are driven by a subpopulation of dedicated stem cells, known as cancer stem cells (CSCs), that exhibit long-tern clonal repopulation and self-renewal capacity. CSCs may regulate tumor initiation, growth, dormancy, metastasis, recurrence and chemoresistance. While autophagy has been proposed as a regulator of the stemness of CSCs, the underlying mechanisms requires further elucidation. Methods The subpopulation of CSCs in human melanoma cell line M14 was established by repetitive enrichments for cells that consistently display anchorage-independent spheroid growth. The stemness properties of the CSCs were confirmed in vitro by the expressions of stemness marker genes, the single-cell cloning assay and the serial spheroid formation assay. Subcutaneous tumor transplantation assay in BALB/c nude mice was performed to test the stemness properties of the CSCs in vivo. The autophagic activity in cells was confirmed by the protein level of LC3 and P62, mRFP-LC3B punta and cytoplasmic accumulation of autolysosomes. The morphology of ER was detected with transmission electron microscopy. Results In the present study, by employing a stable CSC cell line derived from human melanoma cell line M14, we show for the first time that Sec23a inhibits the self-renewal of melanoma CSCs via inactivation of ER-phagy. Mechanistically, inhibition of Sec23a reduces ER stress and consequently FAM134B-induced ER-phagy. Furthermore, TCGA data mining and analysis show that Sec23a is a favorable diagnostic and prognostic marker for human skin cutaneous melanoma (SKCM). Conclusion Herein, this study has elucidated a new mechanism underlying the regulation of autophagy on stemness, i.e. CSCs can exploit the SEC23A/ER-stress/FAM134B/ER-phagy axis for the self-renewal. The results provide new ideas for comprehensive exploration of the regulatory network of CSC self-renewal and new potential targets for CSCs-based therapy strategies for malignant tumors.

The “Big Five” Phytochemicals Targeting Cancer Stem Cells: Curcumin, EGCG, Sulforaphane, Resveratrol and Genistein

2020 ◽  
Vol 27 ◽  
Author(s):  
Cord Naujokat ◽  
Dwight L. McKee
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Recurrence ◽  
Cancer Therapeutics ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Xenograft Mice

: Cancer stem cells (CSCs) constitute a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity, and the ability to give rise to the heterogeneous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to virtually all conventional cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Different pathways and mechanisms that confer resistance and survival of CSCs, including activation of the Wnt/β-catenin, Sonic Hedgehog, Notch, PI3K/Akt/mTOR and STAT3 signaling pathways, expression of aldehyde dehydrogenase 1 (ALDH1) and oncogenic microRNAs, and acquisition of epithelial-mesenchymal transition (EMT), have been identified recently. Certain phytochemicals, in particular curcumin, epigallocatechin-3-gallate (EGCG), sulforaphane, resveratrol and genistein have been shown to interfere with these intrinsic CSC pathways in vitro and in human xenograft mice, leading to elimination of CSCs. Moreover, recent clinical trials have demonstrated therapeutic efficacy of the five phytochemicals, alone or in combination with modern cancer therapeutics, and in various types of cancer. Since current cancer therapies fail to eradicate CSCs, leading to cancer recurrence and progression, targeting of CSCs with phytotochemicals such as curcumin, EGCG, sulforaphane, resveratrol and genistein, combined with each other and/or in combination with conventional cytotoxic drugs and novel cancer therapeutics, may offer a novel therapeutic strategy against cancer.

Cancer Stem Cells Equipped with Powerful Hedgehog Signaling and Better Epigenetic Memory: Avenues to Look for Cancer Therapeutics

2019 ◽  
Vol 19 (11) ◽  
pp. 877-884 ◽  
Author(s):  
Ishita Tandon ◽  
Asawari Waghmode ◽  
Nilesh Kumar Sharma
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Cancer Therapeutics ◽  
Complex Nature ◽  
Epigenetic Memory ◽  
Therapeutic Approaches ◽  
Shh Signaling ◽  
Memory Power

Complex nature of the tumor is depicted at the cellular landscape by showing heterogeneity in the presence of cancer cells, cancer-associated stromal cells, mesenchymal stem cells and cancer stem cells (CSCs). One of the plausible views in cancer formation is suggested as the theory of cancer CSCs that is known as a source of initiation of tumorigenesis. In essence, these powerful CSCs are equipped with high Sonic Hedgehog (SHH) signaling and epigenetic memory power that support various tumor hallmarks. Truly, nature justifies its intent by limiting these stem cells with a potential to turn into CSCs and in turn suppressing the high risk of humans and other organisms. In short, this mini-review addresses the contribution of SHH signaling to allow reprogramming of epigenetic memory within CSCs that support tumor hallmarks. Besides, this paper explores therapeutic approaches to mitigate SHH signaling that may lead to a blockade of the pro-tumor potential of CSCs.

scholarly journals Pharmacological inhibition of polycomb repressive complex-2 activity induces apoptosis in human colon cancer stem cells

2013 ◽  
Vol 319 (10) ◽  
pp. 1463-1470 ◽  
Author(s):  
Yannick D. Benoit ◽  
Mavee S. Witherspoon ◽  
Kristian B. Laursen ◽  
Amel Guezguez ◽  
Marco Beauséjour ◽  
...  
Keyword(s):  
Stem Cells ◽  
Colon Cancer ◽  
Cancer Stem Cells ◽  
Human Colon ◽  
Polycomb Repressive Complex ◽  
Human Colon Cancer ◽  
Polycomb Repressive Complex 2 ◽  
Pharmacological Inhibition ◽  
Colon Cancer Stem Cells

Cancer stem cells niche: A target for novel cancer therapeutics

2013 ◽  
Vol 39 (3) ◽  
pp. 290-296 ◽  
Author(s):  
Shan-Yong Yi ◽  
Yi-Bin Hao ◽  
Ke-Jun Nan ◽  
Tian-Li Fan
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Therapeutics

scholarly journals 3D chromatin architecture and epigenetic regulation in cancer stem cells

2021 ◽  
Author(s):  
Yuliang Feng ◽  
Xingguo Liu ◽  
Siim Pauklin
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cell Formation ◽  
Cancer Therapeutics ◽  
Cellular Transformation ◽  
Cellular Heterogeneity ◽  
Chromatin Dynamics ◽  
Transcriptional Dysregulation ◽  
Chromatin Architecture

AbstractDedifferentiation of cell identity to a progenitor-like or stem cell-like state with increased cellular plasticity is frequently observed in cancer formation. During this process, a subpopulation of cells in tumours acquires a stem cell-like state partially resembling to naturally occurring pluripotent stem cells that are temporarily present during early embryogenesis. Such characteristics allow these cancer stem cells (CSCs) to give rise to the whole tumour with its entire cellular heterogeneity and thereby support metastases formation while being resistant to current cancer therapeutics. Cancer development and progression are demarcated by transcriptional dysregulation. In this article, we explore the epigenetic mechanisms shaping gene expression during tumorigenesis and cancer stem cell formation, with an emphasis on 3D chromatin architecture. Comparing the pluripotent stem cell state and epigenetic reprogramming to dedifferentiation in cellular transformation provides intriguing insight to chromatin dynamics. We suggest that the 3D chromatin architecture could be used as a target for re-sensitizing cancer stem cells to therapeutics.

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