Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer

Sep 21, 2026

Uploaded by Asher

Cancer stem cells constitute a resilient tumor subpopulation that drives differentiation, regeneration, and chemotherapy resistance, often protected by dormancy. Their drug resistance and metastatic potential complicate effective therapeutic targeting, while their survival relies on distinctive metabolic programs. This review clarifies the functional interplay between autophagy and AMPK, showing how autophagy supports energy homeostasis yet can be exploited by CSCs to preserve stemness. It highlights targeting challenges and discusses therapeutic strategies and remaining unanswered questions to identify potential vulnerabilities.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages29

Reading Time1 h 13 min

AccessFree to download

Introduction

Cancer recurrence and the role of cancer stem cells

Metabostemness and metabolic control

Autophagy as a key regulatory process

Autophagy in maintaining stemness

Dual role of autophagy in cancer

AMPK and therapeutic implications

AMPK-driven metabolic reprogramming

Challenges and strategies for targeting

Review Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer Lochana Kovale 1, Manish Kumar Singh 1, Joungmok Kim 2, *,† and Joohun Ha 1, *,† Citation: Kovale, L.; Singh, M.K.; Kim, J.; Ha, J. Role of Autophagy and AMPK in Cancer Stem Cells: Therapeutic Opportunities and Obstacles in Cancer. Int. J. Mol. Sci. 2024, 25, 8647. [https:// doi.org/](https:// doi.org/)[ ](https:// doi.org/)[10.3390/ijms25168647](10.3390/ijms25168647) Academic Editor: Riccardo Alessandro Received: 11 June 2024 Revised: 30 July 2024 Accepted: 7 August 2024 Published: 8 August 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Biochemistry and Molecular Biology, Graduate School, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea; [kovlelochana@gmail.com](kovlelochana@gmail.com) (L.K.); [manishbiochem@gmail.com](manishbiochem@gmail.com) (M.K.S.) 2 Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea * [Correspondence: jok011@khu.ac.kr](Correspondence: jok011@khu.ac.kr) (J.K.); [hajh@khu.ac.kr](hajh@khu.ac.kr) (J.H.); Tel.: +82-2-961-0921 (J.H.)† Co-corresponding author. Abstract: Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5′ adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention. Keywords: cancer stem cells; autophagy; AMPK 1. Introduction Cancer presently stands as the primary cause of premature death and a significant obstacle to global life expectancy, with projections indicating a further increase in its prevalence over the next five decades [1] . In late-stage malignancies, the chance of complete recovery decreases, resulting in reduced survival rates. Thus, quick discovery, diagnosis, and successful treatment are critical for patients’ full recovery and improved quality of life. Patients who have undergone chemotherapy or radiotherapy frequently encounter relapses, with CSCs being identified as one of the contributing factors. CSCs were initially characterized as a subset of cancer cells capable of self-renewal and differentiation into progenitor cancer cells. These cells typically remain dormant and can re-emerge under favorable conditions, contributing to disease recurrence. Tumor heterogeneity an

FAQs

Why are cancer stem cells difficult to target in therapy?

Cancer stem cells are resilient and can survive chemotherapy by maintaining dormancy and exhibiting drug resistance, often leading to relapse and treatment failure.

How does autophagy relate to cancer stem cell stemness?

Autophagy generally supports energy homeostasis, but CSCs can hijack autophagy to maintain stemness and survival under stress.

What role does AMPK play in cancer stem cells?

AMPK helps regulate metabolic reprogramming in harsh tumor environments, contributing to the maintenance of cancer stem cell stemness and survival.

Sep 21, 2026

Uploaded by Asher