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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:Reprogramming of somatic cells to the phenotypic state termed "induced pluripotency" is thought to occur through three consecutive stages: initiation, maturation, and stabilisation. The initiation phase is stochastic but nevertheless very important as it sets the gene expression pattern that permits completion of reprogramming; hence a better understanding of this phase and how this is regulated may provide the molecular cues for improving the reprogramming process. c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPKs) are stress activated MAPK kinases that play an essential role in several processes known to be important for successful completion of the initiation phase such as cellular proliferation, mesenchymal to epithelial transition (MET) and cell cycle regulation. In view of this, we postulated that manipulation of this pathway would have significant impacts on reprogramming of human fibroblasts to induced pluripotent stem cells. Accordingly, we found that key components of the JNK/SAPK signaling pathway increase expression as early as day 3 of the reprogramming process and continue to rise in reprogrammed cells throughout the initiation and maturation stages. Using both chemical inhibitors and RNA interference of MKK4, MKK7 and JNK1, we tested the role of JNK/SAPK signaling during the initiation stage of neonatal and adult fibroblast reprogramming. These resulted in complete abrogation of fully reprogrammed colonies and the emergence of partially reprogrammed colonies which disaggregated and were lost from culture during the maturation stage. Inhibition of JNK/SAPK signaling resulted in reduced cell proliferation, disruption of MET and loss of the pluripotent phenotype, which either singly or in combination prevented establishment of pluripotent colonies. Together these data provide new evidence for an indispensable role for JNK/SAPK signaling to overcome the well-established molecular barriers in human somatic cell induced reprogramming. Stem Cells 2016;34:1198-1212.

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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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