YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Abstract

Background/Aims: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo–Yap pathway in human rectal cancer tumorigenesis and metastasis. Methods: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. Results: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. Conclusion: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy.

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

“…However, MKP1 overexpression interrupted JNK activation and therefore terminated the JNK-CaMKII-Fis1 signalling, favouring mitochondrial homeostasis. This finding is consistent with previous studies [64,65]. In liver cancer, JNK-CaMKII pathway activation is closely associated with mitochondrial malfunction and cancer migration inhibition [22].…”

RETRACTED ARTICLE: Excessive mitochondrial fragmentation triggered by erlotinib promotes pancreatic cancer PANC-1 cell apoptosis via activating the mROS-HtrA2/Omi pathways

“…After it is released into the cytoplasm, HtrA2/Omi can interact with and activate mitochondrial apoptosis in a manner that is dependent on caspase-9 activity [ 11 ]. Notably, an early feature of caspase-9-related apoptosis is the reduction of mitochondrial potential.…”

“…Notably, this conclusion is also supported by other studies. In colorectal cancer, the activation of mitochondrial fission is associated with SW837 cell apoptosis and migration inhibition [ 11 ]. In gastric cancer, abnormal mitochondrial fission contributes to cancer cell oxidative stress and energy undersupply [ 12 ].…”

“…Notably, mitochondrial ROS (mROS) overloading, as a primary result of mitochondrial fragmentation [ 16 ], has been noted in different disease models such as those of gastric cancer [ 17 ], breast cancer [ 18 ], and leukemia [ 19 ]. Subsequently, excessive mitochondrial oxidative injury can activate the HtrA2/Omi-related apoptotic pathway in a manner that is dependent on caspase-9 activity [ 11 ]. This evidence indicates that the downstream effectors of mitochondrial fragmentation include mROS overproduction, HtrA2/Omi upregulation, caspase-9 activation and mitochondrial apoptosis augmentation.…”

The Emerging Role of YAP/TAZ in Tumor Immunity

“…They regulate the activity and functions of immune cells independently of the canonical Hippo pathway (43)(44)(45)(46). Given that YAP/TAZ is a critical effector of Hippo pathway and an important oncoprotein, it plays a pivotal role in tumor progression across numerous tumor types (47)(48)(49)(50). Understanding the immunomodulatory effects of YAP/TAZ in malignant neoplasms is essential and meaningful for the development of novel therapeutic strategies.…”