The role of autophagy in hepatocellular carcinoma: friend or foe

Liu, Lian; Liao, Jiazhi; He, Xingxing; Li, Peiyuan

doi:10.18632/oncotarget.17202

Cited by 128 publications

(116 citation statements)

References 172 publications

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“…However, emerging evidence indicated that the self‐cannibalistic function may be associated with excessive cell death under certain conditions31, 32 Therefore, more and more scholars described the role of autophagy in various pathophysiological processes as a double‐edged sword 33, 34, 35, 36. From the previous study, the autophagy was proved to be a protective role for AKI37, 38 .…”

Section: Discussionmentioning

confidence: 99%

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Zhou

Fan

Zhong

et al. 2018

J Cellular Molecular Medi

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The ability of cisplatin (cis‐diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted people's attention and concern for a long time, but its molecular mechanisms are still widely unknown. We found that the expression of transforming growth factor‐β (TGF‐β)‐activated kinase 1 (TAK1) could be increased in kidneys of mice administrated with cisplatin. Autophagy is an evolutionarily conserved catabolic pathway and is involved in various acute and chronic injuries. Moreover, p38 MAPK (mitogen‐activated protein kinase) and ERK regulate autophagy in response to various stimuli. Therefore, our hypothesis is that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells and thus exacerbating kidney damage. Here, BALB/c mice were intraperitoneally injected with a TAK1 inhibitor and were then administrated with sham or cisplatin at 20 mg/kg by intraperitoneal injection. Compared with mice in the vehicle cisplatin group, mice intraperitoneally injected with a TAK1 inhibitor were found to have lower serum creatinine and less tubular damage following cisplatin‐induced AKI. Furthermore, inhibition of TAK1 reduced p38 and Erk phosphorylation, decreased expression of LC3II and reversed the down‐regulation of P62 expression induced by cisplatin. The hypothesis was verified with tubular epithelial cells administrated with cisplatin in vitro. Finally, p38 inhibitor or ERK inhibitor abated autophagy activation and cell viability reduction in tubular epithelial cells treated with cisplatin plus TAK1 overexpression vector. Taken together, our results show that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells that exacerbates kidney damage.

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Section: Discussionmentioning

confidence: 99%

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Zhou

Fan

Zhong

et al. 2018

J Cellular Molecular Medi

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“…Melatonin affects DNA excision repair cross complementary 1 (ERCC1) protein as well as Beclin‐1 and its autophagic moderator mammalian target of rapamycin (mTOR) (Bennukul et al, ) in a concentration‐dependent manner (Liu & Ryan, ). Beclin‐1 expression is negatively associated with HSC grade (Liu et al, ). MTOR inhibits ATG1 phosphorylation (Liu & Ryan, ).…”

Section: Introductionmentioning

confidence: 99%

Human hepatocellular carcinoma: Protection by melatonin

Mortezaee

2018

Journal Cellular Physiology

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Despite great scientific breakthroughs toward understanding the identity of human hepatocellular carcinoma (HCC) mechanistically, there are still no clinically efficient therapeutic methods for this cancer. Melatonin (N-acetyl-5-methoxytryptamine) is a multi-tasking hormone that has long been known for its anti-cancer activity against various human cancers including HCC, which is a focus of this review. PubMed database was searched for relevant articles with the keywords: hepatocellular carcinoma (HCC), melatonin, apoptosis, proliferation, invasion, angiogenesis, autophagy, oxidative stress, tumor immunity, and mitogen-activated protein kinase (MAPK) focusing on just human cell lines and English language articles. Melatonin inhibits apoptosis resistance and activates both extrinsic and intrinsic pathways of apoptosis in HCC. Melatonin induces ensoplasmic reticulum (ER)- and autophagy-mediated apoptosis in cancer cells. Melatonin works against cancer cell proliferation, motility, and invasiveness by modulating actions of a variety of transcription factors and related pathways. Melatonin also relieves an immunosuppressive state in HCC cancer cells through making a control over tumor-derived exosomes. Both pro-and anti-oxidative functions of melatonin are necessary for combating HCC. Combination of melatonin with chemotherapy could also provide cumulative effects on cancer cells. Melatonin exerts most of these roles by acting on the members of MAPK family.

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“…AKT and ERK play crucial roles in cell proliferation, metastasis, angiogenesis, and drug response. The phosphorylated state of both AKT and ERK is indicative of the activity of tumor signaling (25,26). Moreover, a high expression of both proteins coincides with higher tumor cell viability and proliferation, and lower death in basic experiments, but a poorer prognosis in clinical practice (27).…”

Section: Discussionmentioning

confidence: 99%

Effects of PHA-665752 and vemurafenib combination treatment on inï¿½vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

Zhi

et al. 2018

Oncol Lett

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Abstract. It remains unknown whether blockade of B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E signaling and MET proto-oncogene, receptor tyrosine kinase (c-Met) signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. The present study investigated the effects of the vemurafenib alone and in combination with c-Met inhibitor PHA-665752 on the growth of human CRC cells in vitro and in mouse xenografts. HT-29 and RKO CRC cell lines with BRAF V600E mutations and mice bearing HT-29 xenografts were treated with vemurafenib in the absence or presence of PHA-665752. Cell viability and cycle phase were respectively examined by using the MTT and flow cytometry assay. Immunohistochemistry was conducted to detect the protein expression levels of hepatocyte growth factor (HGF), phosphorylated (p)-c-Met, p-AKT serine/threonine kinase (AKT) and p-extracellular signal-regulated kinase (p-ERK). The MTT assay demonstrated that the growth of RKO and HT-29 cells was inhibited by PHA-665752 in a time-and dose-dependent manner (P<0.05), however no significant suppressive effects were observed with vemurafenib. Relative to the PHA-665752 or vemurafenib stand-alone treatment groups, the combination of PHA-665752 and vemurafenib had a significant inhibitory effect on the proliferation of CRC cell lines (P<0.05). The mean tumor volume in mice treated with vemurafenib in combination with PHA-665752 was significantly smaller compared with those treated with only vemurafenib or PHA-665752 (P<0.05). Flow cytometry assay revealed that the G0/G1 phase frequency was significantly increased in the combination group compared with any other treatment groups (P<0.05). Immunohistochemistry demonstrated that vemurafenib in combination with PHA-665752 effectively induced the expression of p-c-Met, p-AKT and p-ERK, however had no effect on HGF. IntroductionColorectal cancer (CRC) is one of the principal causes of cancer worldwide (1). Unfortunately, even if a 5-year survival prognosis can be given to 90% of patients in the early stages, disappointing treatment outcomes are recorded in subjects with extensive local invasion or distant metastases. Generally, their 5-year survival rate is less than 15% (2) and, even if suitable for receiving adjuvant chemotherapy, disease-related deaths remain stubbornly high.A recent steady stream of important breakthroughs has dramatically improved our understanding of CRC. One such discovery identified the BRAF mutation as common in metastatic CRC patients, especially those with a right-side colon cancer and a poorly differentiated tumor (3). Vemurafenib is a potent and selective inhibitor of mutated BRAF. Chapman et al (4) revealed that vemurafenib achieved 40% response rates in melanoma with a BRAF mutation. However, unlike melanoma, the effect of vemurafenib in CRC patients with a BRAF mutation is often negligible, resulting in a clinical response in only 5% of patients (5). This discrepancy of outcomes suggests that different cancer types may present important variat...

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The role of autophagy in hepatocellular carcinoma: friend or foe

Cited by 128 publications

References 172 publications

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Human hepatocellular carcinoma: Protection by melatonin

Effects of PHA-665752 and vemurafenib combination treatment on inï¿½vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

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