Open AccessDRP1 promotes lactate utilization in KRAS ‐mutant non‐small‐cell lung cancer cells
Author(s) -
Hu Mangze,
Zhao Yu,
Cao Yuejiao,
Tang Qianru,
Feng Ziqin,
Ni Jun,
Zhou Xiaorong
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14603
Subject(s) - kras , biology , cancer research , cancer cell , microbiology and biotechnology , chemistry , cancer , colorectal cancer , genetics
Abstract Metabolic alterations are well documented in various cancers. Non‐small‐cell lung cancers (NSCLCs) preferentially use lactate as the primary carbon source, but the underlying mechanisms are not well understood. We developed a lactate‐dependent cell proliferation assay and found that dynamin‐related protein (DRP1), which is highly expressed in KRAS ‐mutant NSCLC, is required for tumor cells to proliferate and uses lactate as fuel, demonstrating the critical role of DRP1 in the metabolic reprogramming of NSCLC. Metabolic and transcriptional profiling suggests that DRP1 orchestrates a supportive metabolic network to promote lactate utilization and redox homeostasis in lung cancer cells. DRP1 suppresses the production of reactive oxygen species (ROS) and protects cells against oxidative damage by enhancing lactate utilization. Moreover, targeting DRP1 not only reduces HSP90 expression but also enhances ROS‐induced HSP90 cleavage, thus inhibiting activation of mitogen activated protein kinase and PI3K pathways and leading to suppressed lactate utilization and increased ROS‐induced cell death. Taken together, these results suggest that DRP1 is a crucial regulator of lactate metabolism and redox homeostasis in KRAS ‐mutant lung cancer, and that targeting lactate utilization by modulating DRP1 activity might be an effective treatment for lung cancer.