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Mammalian STE20?like kinase 1 regulates pancreatic cancer cell survival and migration through Mfn2?mediated mitophagy.

ABSTRACT: Mammalian STE20-like kinase 1 (MST1) plays an important role in pancreatic cancer progression, but its downstream targets are still unknown. In the present study, our results indicated that MST1 expression was significantly downregulated in pancreatic cancer cell lines (PANC?1, BxPC?3 and HPAC) compared with that in the normal ductal epithelial cell line (hTERT?HPNE). Moreover, MST1 overexpression in PANC?1 cells led to increased apoptosis as determined by MTT and TUNEL assays and inhibited cellular migration. Mechanistically, upregulation of MST1 expression caused mitochondrial dysfunction, decreased ATP production, and activation of the mitochondrial?dependent apoptotic pathway via inhibition of mitofusin 2 (Mfn2)?mediated mitophagy, which ultimately resulted in increased cellular apoptosis and decreased cellular migration. Collectively, the present study demonstrated that MST1 may regulate pancreatic cancer PANC?1 cell survival, invasion and migration through Mfn2?mediated mitophagy, laying the foundation for the exploration of novel therapeutic targets for pancreatic cancer.

SUBMITTER: Hu Y

PROVIDER: S-EPMC7248474 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Mammalian STE20‑like kinase 1 regulates pancreatic cancer cell survival and migration through Mfn2‑mediated mitophagy.

Hu Yongli Y Wang Bing B Wang Lie L Wang Zhenran Z Jian Zhiyuan Z Deng Lin L

Molecular medicine reports 20200428 1

Mammalian STE20-like kinase 1 (MST1) plays an important role in pancreatic cancer progression, but its downstream targets are still unknown. In the present study, our results indicated that MST1 expression was significantly downregulated in pancreatic cancer cell lines (PANC‑1, BxPC‑3 and HPAC) compared with that in the normal ductal epithelial cell line (hTERT‑HPNE). Moreover, MST1 overexpression in PANC‑1 cells led to increased apoptosis as determined by MTT and TUNEL assays and inhibited cell ...[more]

PMID: 32377725

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and/or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour.MethodsWe determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human pancreatic duct epithelial cell line (HPDE). The function of P2X7R in proliferation (BrdU assay), migration (wound assay) and invasion (Boyden chamber with matrigel) was characterized. Furthermore, we studied P2X7R-dependent pore formation (YoPro-1 assay) and cell death (caspase and annexin V / propidium iodide assays).ResultsWe found higher expression of P2X7R protein in PDAC compared to HPDE cells. P2X7R had notable disparate effects on PDAC survival. Firstly, high concentrations of ATP or the specific P2X7R agonist, BzATP, had cytotoxic effects in all cell lines, and cell death was mediated by necrosis. Moreover, the P2X7R-pore antagonist, A438079, prevented ATP-induced pore formation and cell death. Second, in basal conditions and with low concentrations of ATP/BzATP, the P2X7R allosteric inhibitor AZ10606120 reduced proliferation in all PDAC cell lines. P2X7R also affected other key characteristics of cancer cell behavior. AZ10606120 reduced cell migration and invasion in PDAC cell lines compared to that of untreated/vehicle-treated control cells, and stimulation with sub-millimolar concentrations of ATP or BzATP substantially increased cell invasion.ConclusionsPDAC cell lines overexpress P2X7R and the receptor plays crucial roles in cell survival, migration and invasion. Therefore, we propose that drugs targeting P2X7R could be exploited in therapy of pancreatic cancer.

Dataset Information

Mammalian STE20?like kinase 1 regulates pancreatic cancer cell survival and migration through Mfn2?mediated mitophagy.

Publications

Mammalian STE20‑like kinase 1 regulates pancreatic cancer cell survival and migration through Mfn2‑mediated mitophagy.

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