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TGF-? downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade.

ABSTRACT: Transforming growth factor (TGF)-? signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-? promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF-?1 and TGF-?2 to investigate the role of TGF-? downregulation in cancer cell death. We found that the downregulation of TGF-? increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by TGF-? downregulation, which triggered Akt inactivation and NOX4 increase-derived ROS in a cancer cell-type-specific manner. We also revealed the possibility of substantial gene fluctuation in response to TGF-? downregulation related to SAPKs. The expression levels of Trx and GSTM1, which encode inhibitory proteins that bind to ASK1, were reduced, likely a result of the altered translocation of Smad complex proteins rather than from ROS production. Instead, both ROS and ROS-mediated ER stress were responsible for the decrease in interactions between ASK1 and Trx or GSTM1. Through these pathways, ASK1 was activated and induced cytotoxic tumor cell death via p38/JNK activation and (or) induction of ER stress.

SUBMITTER: Han Z

PROVIDER: S-EPMC6283885 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade.

Han Zhezhu Z Kang Dongxu D Joo Yeonsoo Y Lee Jihyun J Oh Geun-Hyeok GH Choi Soojin S Ko Suwan S Je Suyeon S Choi Hye Jin HJ Song Jae J JJ

Experimental & molecular medicine 20181206 12

Transforming growth factor (TGF)-β signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-β promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF-β1 and TGF-β2 to investigate the role of TGF-β downregulation in cancer cell death. We found that the downregulation of TGF-β increased the phosphorylation of several SAPKs, such as p38 ...[more]

PMID: 30523245

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Project description:Angiopoietin-1 (Ang-1) is a well-known endothelial growth factor, but its effects on neurons have yet to be elucidated. We show that Ang-1 is rapidly downregulated in the injured brain after controlled cortical impact (CCI), a mouse experimental traumatic brain injury (TBI) model and in etoposide-induced neuronal apoptosis in vitro. Ang-1 treatment inhibits etoposide-induced upregulation of proapoptotic B-cell lymphoma 2 (Bcl-2) family members Noxa, p53 upregulated modulator of apoptosis (Puma), Bcl-2 interacting mediator of cell death (Bim), and Bcl-2-associated X protein (Bax); reduces markers of caspase-dependent (cytochrome c release/caspase activation) and caspase-independent (apoptosis-inducing factor release) pathways; and limits neuronal cell death. Ang-1 treatment phosphorylates receptors Tunica interna endothelial cell kinase 2 (Tie2), and ?1-integrin and limits the etoposide-induced decrease in protein kinase B (Akt) activity. Blocking Tie2 and ?1-integrin signaling reduces Ang-1 neuroprotective effects. After both TBI and etoposide treatment microRNA (miR)-711 are upregulated, consistent with its putative role as a negative regulator of Ang-1. We show that miR-711 directly targets the Ang-1 messenger RNA (mRNA), decreasing Ang-1 expression. Increased levels of miR-711 and Ang-1 mRNA are found in the RNA-induced silencing complex complex site of miR-mediated degradation of target mRNAs after etoposide treatment and the miR-711mimic downregulates Ang-1. Administration of miR-711 inhibitor elevates Ang-1 after TBI whereas Ang-1 administration increases Akt activation; reduces Puma, Noxa, Bim, and Bax levels; and attenuates caspase-dependent and -independent neuronal apoptosis 24?h after TBI. Ang-1 also attenuates neuronal degeneration, increases gene expression of molecules that maintain blood-brain barrier integrity, and reduces post-traumatic lesion volume/edema 24?h after TBI. Although we only observed short-term neuroprotective effects after Ang-1 administration, miR-711-dependent downregulation of Ang-1, followed by Akt pathway inhibition, may play a role in neuronal cell death after neuronal injury in vitro and after experimental TBI.

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TGF-? downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade.

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TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade.

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