Chloroquine sensitises hypoxic colorectal cancer cells to ROS-mediated cell death via structural disruption of pyruvate dehydrogenase kinase 1

Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We r...

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Published in:	Free radical biology & medicine Vol. 227; pp. 656 - 666
Main Authors:	Mir, Irfan Ahmad, Mir, Hilal Ahmad, Mehraj, Umar, Bhat, Mohd Younus, Mir, Manzoor Ahmad, Dar, Tanveer Ali, Hussain, Mahboob-Ul
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01.02.2025
Subjects:	And apoptosis Apoptosis - drug effects Autophagy - drug effects Cell Hypoxia Cell Proliferation - drug effects Cell Survival - drug effects Chloroquine - pharmacology Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology CQ-Binding CQ-Repositioning Glycolysis Glycolysis - drug effects HCT116 Cells Humans Hypoxia Membrane Potential, Mitochondrial - drug effects Mitochondria - drug effects Mitochondria - metabolism MMP PDK1 Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - chemistry Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Pyruvate Dehydrogenase Acetyl-Transferring Kinase Reactive Oxygen Species - metabolism ROS MMP And apoptosis CQ-Repositioning Colorectal cancer ROS Glycolysis Hypoxia PDK1 CQ-Binding
ISSN:	0891-5849, 1873-4596, 1873-4596
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Abstract	Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We report for the first time that CQ suppresses hypoxia-induced growth and survival of HCT-116 cells by reducing glycolytic capacity and NAD+ production through inhibition of PDK1. Furthermore, in silico and in vitro studies revealed that CQ induces structural alteration in the PDK1 protein, leading to its destabilization and promotes its enhanced degradation by proteases. This degradation is in turn inhibited by the MG-132 protease inhibitor. Moreover, CQ-induced suppression of PDK1 results in mitochondrial damage through excessive production of ROS, as reflected by the reduction in mitochondrial membrane potential, which in turn triggers apoptosis through PARP cleavage and Caspase activation. These findings advocate CQ as a promising repurposable chemotherapeutic for colorectal cancer and a novel inhibitor of PDK1. In absence of Chloroquine-Active PDK1 inhibits activity of pyruvate dehydrogenase complex (PDHC) promoting Warburg effect, which inhibits ROS generation and stimulates cell survival and growth.In presence of Chloroquine –CQ-induced destabilization of PDK1 promotes its degradation, resulting in increased mitochondrial oxidative phosphorylation (OXPHOs) thereby increasing ROS generation and cell death. [Display omitted] •CQ suppresses proliferation of hypoxic HCT-116 cells through the inhibition of anaerobic glycolysis.•This effect of CQ is facilitated by its targeting of PDK1, a kinase crucial for glycolytic reprogramming during hypoxa.•CQ directly binds to PDK1, affecting its overall conformation, stability, and bioavailability.•CQ-mediated loss of PDK1 triggers ROS-dependent apoptosis in HCT-116 cells by reducing mitochondrial activity.
AbstractList	Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We report for the first time that CQ suppresses hypoxia-induced growth and survival of HCT-116 cells by reducing glycolytic capacity and NAD+ production through inhibition of PDK1. Furthermore, in silico and in vitro studies revealed that CQ induces structural alteration in the PDK1 protein, leading to its destabilization and promotes its enhanced degradation by proteases. This degradation is in turn inhibited by the MG-132 protease inhibitor. Moreover, CQ-induced suppression of PDK1 results in mitochondrial damage through excessive production of ROS, as reflected by the reduction in mitochondrial membrane potential, which in turn triggers apoptosis through PARP cleavage and Caspase activation. These findings advocate CQ as a promising repurposable chemotherapeutic for colorectal cancer and a novel inhibitor of PDK1. In absence of Chloroquine-Active PDK1 inhibits activity of pyruvate dehydrogenase complex (PDHC) promoting Warburg effect, which inhibits ROS generation and stimulates cell survival and growth.In presence of Chloroquine –CQ-induced destabilization of PDK1 promotes its degradation, resulting in increased mitochondrial oxidative phosphorylation (OXPHOs) thereby increasing ROS generation and cell death. [Display omitted] •CQ suppresses proliferation of hypoxic HCT-116 cells through the inhibition of anaerobic glycolysis.•This effect of CQ is facilitated by its targeting of PDK1, a kinase crucial for glycolytic reprogramming during hypoxa.•CQ directly binds to PDK1, affecting its overall conformation, stability, and bioavailability.•CQ-mediated loss of PDK1 triggers ROS-dependent apoptosis in HCT-116 cells by reducing mitochondrial activity. Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We report for the first time that CQ suppresses hypoxia-induced growth and survival of HCT-116 cells by reducing glycolytic capacity and NAD+ production through inhibition of PDK1. Furthermore, in silico and in vitro studies revealed that CQ induces structural alteration in the PDK1 protein, leading to its destabilization and promotes its enhanced degradation by proteases. This degradation is in turn inhibited by the MG-132 protease inhibitor. Moreover, CQ-induced suppression of PDK1 results in mitochondrial damage through excessive production of ROS, as reflected by the reduction in mitochondrial membrane potential, which in turn triggers apoptosis through PARP cleavage and Caspase activation. These findings advocate CQ as a promising repurposable chemotherapeutic for colorectal cancer and a novel inhibitor of PDK1.Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We report for the first time that CQ suppresses hypoxia-induced growth and survival of HCT-116 cells by reducing glycolytic capacity and NAD+ production through inhibition of PDK1. Furthermore, in silico and in vitro studies revealed that CQ induces structural alteration in the PDK1 protein, leading to its destabilization and promotes its enhanced degradation by proteases. This degradation is in turn inhibited by the MG-132 protease inhibitor. Moreover, CQ-induced suppression of PDK1 results in mitochondrial damage through excessive production of ROS, as reflected by the reduction in mitochondrial membrane potential, which in turn triggers apoptosis through PARP cleavage and Caspase activation. These findings advocate CQ as a promising repurposable chemotherapeutic for colorectal cancer and a novel inhibitor of PDK1. Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still not known. The present study investigated the effect of CQ on colorectal cancer cells to elucidate the underlying molecular mechanisms. We report for the first time that CQ suppresses hypoxia-induced growth and survival of HCT-116 cells by reducing glycolytic capacity and NAD production through inhibition of PDK1. Furthermore, in silico and in vitro studies revealed that CQ induces structural alteration in the PDK1 protein, leading to its destabilization and promotes its enhanced degradation by proteases. This degradation is in turn inhibited by the MG-132 protease inhibitor. Moreover, CQ-induced suppression of PDK1 results in mitochondrial damage through excessive production of ROS, as reflected by the reduction in mitochondrial membrane potential, which in turn triggers apoptosis through PARP cleavage and Caspase activation. These findings advocate CQ as a promising repurposable chemotherapeutic for colorectal cancer and a novel inhibitor of PDK1.
Author	Mir, Manzoor Ahmad Mir, Irfan Ahmad Hussain, Mahboob-Ul Bhat, Mohd Younus Mehraj, Umar Dar, Tanveer Ali Mir, Hilal Ahmad
Author_xml	– sequence: 1 givenname: Irfan Ahmad orcidid: 0009-0007-7477-5713 surname: Mir fullname: Mir, Irfan Ahmad organization: Department of Biotechnology, School of Biological Sciences, University of Kashmir, Srinagar, 190006, India – sequence: 2 givenname: Hilal Ahmad surname: Mir fullname: Mir, Hilal Ahmad organization: Department of Biotechnology, School of Biological Sciences, University of Kashmir, Srinagar, 190006, India – sequence: 3 givenname: Umar surname: Mehraj fullname: Mehraj, Umar organization: Department of Pathology, Duke University, Durham, NC 27710, USA – sequence: 4 givenname: Mohd Younus surname: Bhat fullname: Bhat, Mohd Younus organization: Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, 190006, India – sequence: 5 givenname: Manzoor Ahmad surname: Mir fullname: Mir, Manzoor Ahmad organization: Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, 190006, J&K, India – sequence: 6 givenname: Tanveer Ali surname: Dar fullname: Dar, Tanveer Ali organization: Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, 190006, India – sequence: 7 givenname: Mahboob-Ul orcidid: 0000-0002-1335-1489 surname: Hussain fullname: Hussain, Mahboob-Ul email: Mahboob@uok.edu.in organization: Department of Biotechnology, School of Biological Sciences, University of Kashmir, Srinagar, 190006, India
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Keywords	MMP And apoptosis CQ-Repositioning Colorectal cancer ROS Glycolysis Hypoxia PDK1 CQ-Binding
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Snippet	Chloroquine (CQ), an autophagy antagonist, has been recently explored as a repurposable medicine for cancer; however the exact mechanism of its action is still...
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SubjectTerms	And apoptosis Apoptosis - drug effects Autophagy - drug effects Cell Hypoxia Cell Proliferation - drug effects Cell Survival - drug effects Chloroquine - pharmacology Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology CQ-Binding CQ-Repositioning Glycolysis Glycolysis - drug effects HCT116 Cells Humans Hypoxia Membrane Potential, Mitochondrial - drug effects Mitochondria - drug effects Mitochondria - metabolism MMP PDK1 Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - chemistry Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Pyruvate Dehydrogenase Acetyl-Transferring Kinase Reactive Oxygen Species - metabolism ROS
Title	Chloroquine sensitises hypoxic colorectal cancer cells to ROS-mediated cell death via structural disruption of pyruvate dehydrogenase kinase 1
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