Phospholipase D1-regulated autophagy supplies free fatty acids to counter nutrient stress in cancer cells.
Cancer cells utilize flexible metabolic programs to maintain viability and proliferation under stress conditions including nutrient deprivation. Here we report that phospholipase D1 (PLD1) participates in the regulation of metabolic plasticity in cancer cells. PLD1 activity is required for cancer cell survival during prolonged glucose deprivation. Blocking PLD1 sensitizes cancer cells to glycolysis inhibition by 2-deoxy-D-glucose (2-DG) and results in decreased autophagic flux, enlarged lysosomes, and increased lysosomal pH. Mechanistically, PLD1-regulated autophagy hydrolyzes bulk membrane phospholipids to supply fatty acids (FAs) for oxidation in mitochondria. In low glucose cultures, the blockade of fatty acid oxidation (FAO) by PLD1 inhibition suppresses adenosine triphosphate (ATP) production and increases reactive oxygen species (ROS), leading to cancer cell death. In summary, our findings reveal a novel role of PLD1 in sustaining cancer cell survival during metabolic stress, and suggest PLD1 as a potential target for anticancer metabolism therapy.
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.|Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Ming
M
Cai
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Jingquan
J
He
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Jian
J
Xiong
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Li Wei Rachel
LW
Tay
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Ziqing
Z
Wang
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Colin
0000-0002-7834-1417
C
Rog
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Jingshu
J
Wang
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Yizhao
Y
Xie
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Guobin
G
Wang
Department of Dermatology, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1194, Japan.
Yoshiko
Y
Banno
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Feng
F
Li
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Michael
M
Zhu
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Guangwei
0000-0003-4193-6975
G
Du
D000468:Alkalies / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D066292:Lipid Droplets / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000468:Alkalies; D005230:Fatty Acids, Nonesterified; D008563:Membrane Lipids; D010743:Phospholipids; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D; C106801:phospholipase D1; D005947:Glucose