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Targeting redox regulation and autophagy systems in cancer stem cells

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Abstract

Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).

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Abbreviations

CSCs:

Cancer stem cells

ROS:

Reactive oxygen species

O2− :

Superoxide

H2O2 :

Hydrogen peroxide

OH• :

Hydroxyl radical

NADPH:

Reduced nicotinamide adenine dinucleotide phosphate

HSCs:

Haematopoietic stem cells

EMT:

Epithelial-mesenchymal transition

PIP3:

Phosphatidylinositol 3,4,5-trisphosphate

PIP2:

Phosphatidylinositol 4,5-bisphosphate

HIF-1:

Hypoxia-inducible factor-1

Keap1:

Kelch-like ECH-associated protein 1

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

LSCs:

Leukemic stem cells

SODs:

Superoxide dismutases

Nrf2:

Nuclear factor erythroid 2-related factor

GSH:

Glutathione

ATM:

Ataxia telangiectasia mutation

PI3K:

Phosphoinositide 3-kinase

EMT:

Epithelial-mesenchymal transition

JNK:

C-Jun N-terminal kinase

AML:

Acute myelogenous leukemia

Trx:

Thioredoxin

TrxR:

Thioredoxin reductase

Grx:

Glutaredoxin

Prdx:

Peroxiredoxins

VEGF:

Vascular endothelial growth factor

TXNIP:

Thioredoxin-interacting protein

COX:

Cyclooxygenase

FOXO:

Forkhead homeobox type O

PHDs:

Prolyl hydroxylase domain proteins

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Acknowledgements

We would also like to thank –Kaneez Fatima and Shariqa Aisha (CSIR-IIIM, India) for critically reading the manuscript, and our colleagues particularly Dr. Reyaz Hassan (University of Kashmir, India), Dr. Abubakar Wani (St. Jude Children's Research Hospital, US) for their fruitful discussions.  CSIR for providing publication approval-Institutional publication ID No. CSIR-IIIM/IPR/00475.

Funding

Funding for FM laboratory was provided by the Council of Scientific and Industrial Research (CSIR) India fellowship, a grant from the Department of Biotechnology Ministry of Science and Technology (DBT) (BT/IN/Swiss/48/FM/2018–19). CSIR-SRF budget head for providing fellowship to SK, SR is the recipient of DBT-Ramalingaswami, Government of India.

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  1. Sameer Ullah Khan and Sheikh Rayees contributed equally.

Authors and Affiliations

  1. Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Srinagar, 190005, India

    Sameer Ullah Khan, Pankaj Sharma & Fayaz Malik

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Sameer Ullah Khan & Fayaz Malik

  3. PK PD Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India

    Sheikh Rayees

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  1. Sameer Ullah Khan
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Contributions

FM supervised the work; SK conceived the idea; SK designed the work; SK, SR, and PS wrote the manuscript; SK, and FM edited the manuscript; SR prepared Fig. 1 and SK prepared Figs. 2 and 3; FM and SK read and approved the final manuscript.

Fig. 2
figure 2

A model of hypoxia and autophagy induction maintains cancer stem cell survival. Cancer and cancer stem cells under hypoxia adaptively activate HIF-1 alpha-mediated autophagy that consequently supports their survival

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2,

Fig. 3
figure 3

Cancer stem cells sustain mitochondrial health and activity. Cancer stem cells under hypoxia cause metabolic reprogramming and maintain the survival and energetics of cells by activating mitophagy of damaged or excessive mitochondria. Moreover, CSCs activate the antioxidant machinery to remove accumulated genotoxic mitochondria ROS in the cells

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3.

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Correspondence to Fayaz Malik.

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Khan, S.U., Rayees, S., Sharma, P. et al. Targeting redox regulation and autophagy systems in cancer stem cells. Clin Exp Med 23, 1405–1423 (2023). https://doi.org/10.1007/s10238-022-00955-5

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