PNO1 regulates autophagy and apoptosis of hepatocellular carcinoma via the MAPK signaling pathway

Han, Zhiqiang; Liu, Dongming; Chen, Lu; He, Yuchao; Tian, Xiangdong; Qi, Lisha; Chen, Liwei; Luo, Yi; Chen, Ziye; Hu, Xiaomeng; Li, Guangtao; Zhan, Linlin; Wang, Yu; Li, Qiang; Chen, Peng; Liu, Zhiyong; Guo, Hua

doi:10.1038/s41419-021-03837-y

Cited by 28 publications

(27 citation statements)

References 60 publications

(59 reference statements)

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“…Our previous study has shown that PNO1 is associated with the progression of various cancers, including HCC [ 15 ] and lung adenocarcinoma [ 16 ]. We further explored the molecular mechanism of PNO1 in regulating the malignant progression of HCC by performing differential protein enrichment analysis, which suggested that PNO1 was significantly associated with ferroptosis (Fig.…”

Section: Resultsmentioning

confidence: 99%

PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma

Han

et al. 2022

Cell Death Dis

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Effective strategies for hepatocellular carcinoma, which is the second leading cause of death worldwide, remain limited. A growing body of emerging evidence suggests that ferroptosis activation is a novel promising approach for the treatment of this malignancy. Nevertheless, the potential therapeutic targets and molecular mechanisms of ferroptosis remain elusive. In this study, we found that PNO1 is a bona fide inhibitor of ferroptosis and that autophagy induced by PNO1 promotes cystine/glutamate antiporter SLC7A11 while increasing the synthesis and accumulation of intracellular glutamate. This increase is followed by an equally proportional addition in cystine uptake, which consequently enhances system Xc- activity that leads to the inhibition of ferroptosis. In the maintenance of redox homeostasis, system Xc- activated via PNO1-autophagy metabolism is responsible for maintaining cysteine for glutathione (GSH) synthesis, and the final GSH metabolic reprogramming protects HCC cells from ferroptosis. The combination of PNO1 inhibition with drugs causing ferroptosis induction, particularly sorafenib, the first-line drug associated with ferroptosis in liver cancer shows therapeutic promise in vitro and in vivo. Together, our findings indicated that PNO1 protects HCC cells from ferroptotic death through autophagy-mediated GSH metabolic remodeling, and we identified a candidate therapeutic target that may potentiate the effect of ferroptosis-based antitumor therapy.

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Section: Resultsmentioning

confidence: 99%

PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma

Han

et al. 2022

Cell Death Dis

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“…Previously, our group found that cPLA2α [ 18 , 19 ] and PNO1 [ 20 ] play a key role in the malignant progression of HCC. Interestingly, we examined the whole transcriptome of cells with different levels of cPLA2α and PNO1 and found that with the decrease of cPLA2α and PNO1, the expression of DNAJC24, a heat shock protein, also decreased (Fig.…”

Section: Resultsmentioning

confidence: 99%

DNAJC24 is a potential therapeutic target in hepatocellular carcinoma through affecting ammonia metabolism

Liu

et al. 2022

Cell Death Dis

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Evolutionarily conserved heat shock proteins are involved in the heat shock response of cells in response to changes in the external environment. In normal tissues, heat shock proteins can help cells survive in a rapidly changing environment. Likewise, in malignant tumors heat shock proteins may help tumor cells cope with external stresses as well as the stress of treatment. In this way they become accomplices of malignant tumors. Here we demonstrated for the first time that high expression of DNAJC24 (a heat shock protein) shortens survival in patients with HCC by immunohistochemical staining of 167 paired hepatocellular carcinomas and paraneoplastic tissues as well as data from public databases. In vitro experiments demonstrated that stimuli such as hypoxia, starvation and heat could upregulate DNAJC24 expression in HCC cells through transcriptional regulation of HSF2, and high expression of DNAJC24 in HCC cells could promote the proliferation and motility of HCC cells. In addition, we also verified that targeting DNAJC24 under normal culture conditions can affect the proliferation and autophagy of HCC cells by interfering with ammonia metabolism, thereby inhibiting the malignant progression of HCC. Overall, we suggested that DNAJC24 may become a new target for the treatment of HCC.

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“…Apoptosis, also called programmed cell death, is a highly ordered and orchestrated cell death process [ 34 ]. Autophagy and apoptosis are two different kinds of programmed cell death and play critical roles in tumorigenesis and cancer progression [ 35 ]. In a previous study, triggering apoptosis inhibited cancer cell survival and proliferation [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

BRAF-activated WT1 contributes to cancer growth and regulates autophagy and apoptosis in papillary thyroid carcinoma

Chen

Lin

Lin³

et al. 2022

J Transl Med

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Background Papillary thyroid carcinoma (PTC) is one of most prevalent malignant endocrine neoplasms, and it is associated with a high frequency of BRAF gene mutations, which lead to lymphatic metastasis and distant metastasis that promote tumor progression. The molecular mechanism of PTC and the role of BRAF mutation in PTC progression and development need to be further elucidated. Methods In this study, a comprehensive bioinformatics analysis was performed to identify the differentially expressed genes and signaling pathways in thyroid cancer patients carrying mutant BRAF. Then, we confirmed the prognostic role of WT1 in thyroid cancer patients. Immunohistochemistry was performed to measure the expression profile of WT1 in PTC tissue. Lentivirus shWT1 was transfected into BRAFV600E (mutant) PTC cells to stably inhibit WT1 expression. CCK-8, EdU, immunofluorescence, colony formation, cell migration, cell wound healing, apoptosis and autophagy assays were performed to assess the biological functions of WT1 in BRAFV600E PTC cells. RNA sequencing, immunohistochemistry and immunoblotting were performed to explore the molecular mechanism of WT1 in BRAFV600E PTC cells. Results The results confirmed that “epithelial cell proliferation”, “apoptosis” and “selective autophagy” were closely associated with this BRAF mutant in these thyroid cancer patients. Knocking down BRAF-activated WT1 effectively inhibited the proliferation and migration of BRAFV600E PTC cells. Silencing WT1 significantly inhibited autophagy and promoted the apoptosis of BRAFV600E PTC cells. Mechanistic investigations showed that silencing WT1 expression remarkably suppressed the AKT/mTOR and ERK/P65 signaling pathways in BRAFV600E PTC cells. Conclusion All these results indicate that WT1 is a promising prognostic biomarker and facilitates PTC progression and development of cells carrying the BRAFV600E mutation.

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PNO1 regulates autophagy and apoptosis of hepatocellular carcinoma via the MAPK signaling pathway

Cited by 28 publications

References 60 publications

PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma

PNO1 inhibits autophagy-mediated ferroptosis by GSH metabolic reprogramming in hepatocellular carcinoma

DNAJC24 is a potential therapeutic target in hepatocellular carcinoma through affecting ammonia metabolism

BRAF-activated WT1 contributes to cancer growth and regulates autophagy and apoptosis in papillary thyroid carcinoma

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