Abstract
BackgroundMitochondrial fragmentation drastically regulates the viability of pancreatic cancer through a poorly understood mechanism. The present study used erlotinib to activate mitochondrial fragmentation and then investigated the downstream events that occurred in response to mitochondrial fragmentation.MethodsCell viability and apoptosis were determined via MTT assay, TUNEL staining and ELISA. Mitochondrial fragmentation was measured via an immunofluorescence assay and qPCR. siRNA transfection and pathway blockers were used to perform the loss-of-function assays.ResultsThe results of our study demonstrated that erlotinib treatment mediated cell apoptosis in the PANC-1 pancreatic cancer cell line via evoking mitochondrial fragmentation. Mechanistically, erlotinib application increased mitochondrial fission and reduced mitochondrial fusion, triggering mitochondrial fragmentation. Subsequently, mitochondrial fragmentation caused the overproduction of mitochondrial ROS (mROS). Interestingly, excessive mROS induced cardiolipin oxidation and mPTP opening, finally facilitating HtrA2/Omi liberation from the mitochondria into the cytoplasm, where HtrA2/Omi activated caspase-9-dependent cell apoptosis. Notably, neutralization of mROS or knockdown of HtrA2/Omi attenuated erlotinib-mediated mitochondrial fragmentation and favored cancer cell survival.ConclusionsTogether, our results identified the mROS-HtrA2/Omi axis as a novel signaling pathway that is activated by mitochondrial fragmentation and that promotes PANC-1 pancreatic cancer cell mitochondrial apoptosis in the presence of erlotinib.
Highlights
Mitochondrial fragmentation drastically regulates the viability of pancreatic cancer through a poorly understood mechanism
Compared to the control group, erlotinib treatment reduced the viability of PANC-1 cells (Fig. 1a, b), and this effect was achieved in a dose-dependent manner
Different doses of erlotinib were added to the medium of PANC-1 cells. b LDH release was used to evaluate the cell death in PANC-1 cells in the presence of erlotinib. c The MTT assay for PaCa-2 cells in the presence of erlotinib treatment. d LDH release was used to evaluate the cell death in PaCa-2 cells in the presence of erlotinib. e TUNEL staining for apoptotic PANC-1 cells and PaCa-2 cells
Summary
Mitochondrial fragmentation drastically regulates the viability of pancreatic cancer through a poorly understood mechanism. A recent study has reported that pancreatic cancer death, proliferation and metastasis are modulated by mitochondrial homeostasis, especially mitochondrial fission [10]. Excessive mitochondrial fission induces cancer cell oxidative injury and subsequently mediates mitochondrial ATP depletion; this effect impairs PANC-1 cell proliferation and evokes mitochondrial apoptosis [10]. This conclusion is supported by other studies. Drp1-mediated mitochondrial fission suppresses breast cancer cell invasion [13]. This information indicates that mitochondrial fission has a well-characterized role in the regulation of cancer viability. The downstream molecular events of mitochondrial fission activation remain to be discovered
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