DRP1 upregulation promotes pancreatic cancer growth and metastasis through increased aerobic glycolysis

Abstract

Background: Mitochondrial shape is dynamically changed by fusion and fission processes in cells, and dysfunction of this process has become one of the emerging hallmarks of cancer. However, the expression patterns and biological effects of mitochondrial fission and fusion proteins in pancreatic cancer (PC) are still unclear. Methods: The expressions of mitochondrial fission and fusion proteins were first evaluated by quantitative reverse transcription polymerase chain reaction and western blot analysis in both PC cell lines and tissue samples. In addition, the biologic functions of the differentially expressed proteins in PC cell growth and metastasis both in vitro and in vivo and their potential underlying mechanisms were systematically explored. Results: We first found that DRP1 was substantially upregulated in PC cell lines and tissue samples mainly due to the downregulation of miR-29a, which contributed to the poor survival of PC patients. DRP1 promoted the growth and metastasis of PC cells both in vitro and in vivo by inducing G1-S cell cycle transition and matrix metalloproteinase 2 secretion. Mechanistic investigations revealed that increased DRP1 upregulation-mediated mitochondrial fission and subsequently enhanced aerobic glycolysis were involved in the promotion of growth and metastasis by DRP1 in PC cells. Conclusions: Our findings demonstrate that mitochondrial fusion protein DRP1 plays a critical oncogenic role in PC cells by enhancing aerobic glycolysis, which could serve as a novel therapeutic target for PC treatment. bs_bs_banner DRP1 promotes PC growth and metastasis J Liang et al. DRP1 promotes PC growth and metastasis J Liang et al.

Comparative untargeted metabolomic profiling of induced mitochondrial fusion in pancreatic cancer

“…Purine metabolism was most affected by indirectly inducing fusion with knockout of Drp1 (Impact = 0.22, Percent Affected = 15.2%); though, still moderately altered via direct fusion with Tet-On Mfn2 (Impact = 0.14, Percent Affected = 10.6%) and pharmacologic fusion with Leflunomide (Impact = 0.10, Percent Affected = 9.1%, Table 5). Both carbohydrate metabolism sub-pathways, PPP, and glycolysis were modestly impacted across the three groups, but knockdown of Drp1 in particular had more impact on glycolysis/gluconeogenesis (Impact = 0.11, Percent Affected = 11.5%), supporting recent findings that Drp1 promotes metabolic changes through glycolysis to drive PDAC tumorigenesis (Table 5) [7,15]. The main pathway that had an impact greater than 0.28 across the Tet-On Mfn2, sgDrp1, and Leflunomide groups was alanine, aspartate, and glutamate metabolism with more than 21.4% of the pathway appearing significantly altered (Table 5).…”

Comparative Untargeted Metabolomic Profiling of Induced Mitochondrial Fusion in Pancreatic Cancer

“…Purine metabolism was most affected by indirectly inducing fusion with knockout of Drp1 (Impact = 0.22, Percent Affected = 15.2%); though, still moderately altered via direct fusion with Tet-On Mfn2 (Impact = 0.14, Percent Affected = 10.6%) and pharmacologic fusion with leflunomide (Impact = 0.10, Percent Affected = 9.1%, Table 5 ). Both carbohydrate metabolism sub-pathways, PPP and glycolysis, were modestly impacted across the three groups, but knockdown of Drp1 in particular had more impact on glycolysis/gluconeogenesis (Impact = 0.11, Percent Affected = 11.5%), supporting recent findings that Drp1 promotes metabolic changes through glycolysis to drive PDAC tumorigenesis ( Table 5 ) [ 7 , 18 ]. The main pathway that had an impact greater than 0.28 across the Tet-On Mfn2, sgDrp1, and Leflunomide groups was alanine, aspartate, and glutamate metabolism with more than 21.4% of the pathway appearing significantly altered ( Table 5 ).…”

Mitochondrial Dynamics Related Genes -MFN1, MFN2 and DRP1 Polymorphisms are Associated with Risk of Lung Cancer

“… 35 In addition, Liang et al demonstrated that DRP1 was upregulated in pancreatic cancer and let to more mitochondrial fission and enhanced aerobic glycolysis, which resulting in cancer cell growth and metastasis. 36 In the present study, we identified that DRP1 -rs879255689 was related to elevated risk of lung cancer. Rs879255689 is a missense variant and led to Gly379Lys, therefore, we speculated that this variant may change the mitochondrial fission and dynamics of lung cancer patients and participant in the development of the disease.…”