DRP1 promotes lactate utilization in <i>KRAS</i>‐mutant non‐small‐cell lung cancer cells

Hu, Mangze; Zhao, Yu; Cao, Yuejiao; Tang, Qianru; Feng, Ziqin; Ni, Jun; Zhou, Xiaorong

doi:10.1111/cas.14603

Cited by 15 publications

(12 citation statements)

References 42 publications

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“…Studies have revealed that CRS activates glial cells to release proinflammatory factors, such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNF- α) ( Deak et al, 2015 ), which in turn promotes apoptosis, ultimately leading to apoptosis. BAX is a proapoptotic protein belonging to the Bcl-2 family, and it acts in conjunction with Drp1 to increase mitochondrial membrane permeability and division, which facilitates the release of cytochrome c (Cyt C) from the mitochondria into the cytoplasm ( Reed, 1997 ; Sugioka et al, 2004 ; Hu et al, 2020 ). CREB serves an important role in neuronal regeneration, synaptic growth, learning, and memory.…”

Section: Introductionmentioning

confidence: 99%

The effects of fresh Gastrodia elata Blume on the cognitive deficits induced by chronic restraint stress

et al. 2022

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Chronic restraint stress (CRS) is a classic animal model of stress that can lead to various physiological and psychological dysfunctions, including systemic neuroinflammation and memory deficits. Fresh Gastrodia elata Blume (FG), the unprocessed raw tuber of Gastrodia elata Blume, has been reported to alleviate the symptoms of headache, convulsions, and neurodegenerative diseases, while the protective effects of FG on CRS-induced cognitive deficits remain unclear. This work aimed to evaluate the effects of FG on CRS-induced cognitive deficits through multiplex animal behavior tests and to further explore the related mechanism by observing the expression of mitochondrial apoptosis-related proteins in the mouse hippocampus. In in vivo experiments, mice were subjected to the object location recognition test (OLRT), new object recognition test (NORT), Morris water maze test (MWMT), and passive avoidance test (PAT) to evaluate the learning and memory ability. In in vitro experiments, the expression of the AKT/CREB pathway, the fission- and apoptosis-related proteins (Drp1, Cyt C, and BAX), and the proinflammatory cytokines’ (TNF‐α and IL‐1β) level in the hippocampus was examined. Our results demonstrated that in spontaneous behavior experiments, FG significantly improved the cognitive performance of CRS model mice in OLRT (p < 0.05) and NORT (p < 0.05). In punitive behavior experiments, FG shortened the escape latency in long-term spatial memory test (MWMT, p < 0.01) and prolonged the latency into the dark chamber in non-spatial memory test (PAT, p < 0.01). Biochemical analysis showed that FG treatment significantly suppressed CRS‐induced Cyt C, Drp1, and BAX activation (p < 0.001, p < 0.01 and p < 0.05), promoted the CREB, p-CREB, AKT, and p-AKT level (p < 0.05, p < 0.01 and p < 0.001), and inhibited the CRS‐induced proinflammatory cytokines (TNF‐α and IL‐1β, p < 0.05 and p < 0.001) level in the hippocampus. Taken together, these results suggested that FG could attenuate cognitive deficits induced by CRS on multiple learning and memory behavioral tests.

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Section: Introductionmentioning

confidence: 99%

The effects of fresh Gastrodia elata Blume on the cognitive deficits induced by chronic restraint stress

et al. 2022

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“…Specifically, PINK1 -/- cells contained 29.2% fragmented mitochondria compared with 77.7% in the vector group ( Figure 6 ). It has been reported previously that upon Drp1 deletion, the mitochondrial morphology in HCT116 cells was more intermediate ( 48 – 50 ). In our study, we inhibited Drp1 expression in HCT116 cells by small interfering RNA (siRNA), and the knockdown efficacy was determined by western blot ( Figure S4C ) .…”

Section: Resultsmentioning

confidence: 70%

Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission

et al. 2022

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Mitochondrial metabolism and dynamics (fission and fusion) critically regulate cell survival and proliferation, and abnormalities in these pathways are implicated in both neurodegenerative disorders and cancer. Mitochondrial fission is necessary for the growth of mutant Ras-dependent tumors. Here, we investigated whether loss of PTEN-induced kinase 1 (PINK1) - a mitochondrial kinase linked to recessive familial Parkinsonism - affects the growth of oncogenic Ras-induced tumor growth in vitro and in vivo. We show that RasG12D-transformed embryonic fibroblasts (MEFs) from PINK1-deficient mice display reduced growth in soft agar and in nude mice, as well as increased necrosis and decreased cell cycle progression, compared to RasG12D-transformed MEFs derived from wildtype mice. PINK1 re-expression (overexpression) at least partially rescues these phenotypes. Neither PINK1 deletion nor PINK1 overexpression altered Ras expression levels. Intriguingly, PINK1-deficient Ras-transformed MEFs exhibited elongated mitochondria and altered DRP1 phosphorylation, a key event in regulating mitochondrial fission. Inhibition of DRP1 diminished PINK1-regulated mitochondria morphological changes and tumor growth suggesting that PINK1 deficiency primarily inhibits Ras-driven tumor growth through disturbances in mitochondrial fission and associated cell necrosis and cell cycle defects. Moreover, we substantiate the requirement of PINK1 for optimal growth of Ras-transformed cells by showing that human HCT116 colon carcinoma cells (carrying an endogenous RasG13D mutation) with CRISPR/Cas9-introduced PINK1 gene deletions also show reduced mitochondrial fission and decreased growth. Our results support the importance of mitochondrial function and dynamics in regulating the growth of Ras-dependent tumor cells and provide insight into possible mechanisms underlying the lower incidence of cancers in Parkinson’s disease and other neurodegenerative disorders.

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“…Consistent results were obtained in the KRas mutant non-small-cell lung cancer (NSCLC), where DRP1 orchestrated a metabolic rewiring to promote lactate utilization and ROS production suppression [ 62 ]. In the same type of tumor, DRP1 was involved in metabolic rearrangements that favored resistance to chemotherapy [ 63 ].…”

Section: Fusion and Fission Event In The Onset And Progression Of mentioning

confidence: 66%

“The Loss of Golden Touch”: Mitochondria-Organelle Interactions, Metabolism, and Cancer

Audano

Pedretti

Ligorio

et al. 2020

Cells

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Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and membrane contact sites, to regulate energy metabolism, biosynthetic processes, apoptosis, and cell turnover. Tumorigenesis is often associated with mitochondrial dysfunction, which could likely be the result of an altered interaction with different cell organelles or structures. The purpose of the present review is to provide an updated overview of the links between inter-organellar communications and interactions and metabolism in cancer cells, with a focus on mitochondria. The very recent publication of several reviews on these aspects testifies the great interest in the area. Here, we aim at (1) summarizing recent evidence supporting that the metabolic rewiring and adaptation observed in tumors deeply affect organelle dynamics and cellular functions and vice versa; (2) discussing insights on the underlying mechanisms, when available; and (3) critically presenting the gaps in the field that need to be filled, for a comprehensive understanding of tumor cells’ biology. Chemo-resistance and druggable vulnerabilities of cancer cells related to the aspects mentioned above is also outlined.

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DRP1 promotes lactate utilization in KRAS‐mutant non‐small‐cell lung cancer cells

Cited by 15 publications

References 42 publications

The effects of fresh Gastrodia elata Blume on the cognitive deficits induced by chronic restraint stress

The effects of fresh Gastrodia elata Blume on the cognitive deficits induced by chronic restraint stress

Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission

“The Loss of Golden Touch”: Mitochondria-Organelle Interactions, Metabolism, and Cancer

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