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Objective To investigate the effects of farnesyl-diphosphate farnesyltransferase 1 (FDFT1) on the growth of colorectal cancer (CRC) cell line MC-38 in vitro and in mouse models of colorectal peritoneal metastasis and xenograft tumor. Methods The expression of FDFT1 in 275 CRC samples and 349 normal tissue samples, as well as the immunohistochemical expression level of FDFT1 in human CRC tissues were analyzed using online databases Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas, respectively. FDFT1-silenced CRC cell line MC-38 was constructed by lentivirus-mediated short hairpin RNA (shRNA) to obtain stable cells with low expression of FDFT1 (sh-FDFT1), and blank control cells (sh-NC) was also constructed. The knockdown effect was subsequently verified by Western blotting and RT-qPCR. Cell counting kit-8 (CCK-8) assay, flow cytometry and transwell assay were performed to observe the effects of FDFT1 knockdown on the proliferation, apoptosis and migration of MC-38 cells, respectively. In addition, intraperitoneal implantation models of colorectal cancer were established using C57BL/6 mice and severe immunodeficient NCG mice, and subcutaneous transplantation tumor model was also constructed using C57BL/6 mice. The effects of FDFT1 silencing on tumor growth in vivo were observed in 14 d after transplantation. Results Database analysis showed that FDFT1 expression was higher in CRC tissues than normal tissues (P < 0.05), and immunohistochemical results also confirmed that FDFT1 was highly expressed in CRC tissues. There were no significant alterations in the proliferation, apoptosis and migration of MC-38 cells after knockdown of FDFT1. Although FDFT1 silencing obviously inhibited the tumor growth in both intraperitoneal implantation and subcutaneous xenograft models of CRC in C57BL/6 mice (P < 0.05), the colorectal peritoneal metastasis model of NCG mice presented no difference in tumor growth after silencing FDFT1 (P>0.05). Conclusion FDFT1 depends on the tumor immune microenvironment in the promotion of the growth of CRC cells in vivo.

Although autophagy is most critical for survival of cancer cells, especially in fast-growing tumors, the mechanism remains to be fully characterized. Herein we report that PSMD10/gankyrin promotes autophagy in hepatocellular carcinoma (HCC) in response to starvation or stress through 2 complementary routes. PSMD10 was physically associated with ATG7 in the cytoplasm, and this association was enhanced by initial nutrient deprivation. Subsequently, PSMD10 translocated into the nucleus and bound cooperatively with nuclear HSF1 (heat shock transcription factor 1) onto the ATG7 promoter, upregulated ATG7 expression in the advanced stage of starvation. Intriguingly, the type of PSMD10-mediated autophagy was independent of the proteasome system, although PSMD10 has been believed to be an indispensable chaperone for assembly of the 26S proteasome. A significant correlation between PSMD10 expression and ATG7 levels was detected in human HCC biopsies, and the combination of these 2 parameters is a powerful predictor of poor prognosis. The median survival of sorafenib-treated HCC patients with high expression of PSMD10 was much shorter than those with low expression of PSMD10. Furthermore, PSMD10 augmented autophagic flux to resist sorafenib or conventional chemotherapy, and inhibition of autophagy suppressed PSMD10-mediated resistance. We conclude that these results present a novel mechanism involving modulation of ATG7 by PSMD10 in sustaining autophagy, promoting HCC cell survival against starvation or chemotherapy. Targeting of PSMD10 might therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to drugs.

As a newly identified type of programmed cell death, cuproptosis may have an impact on cancer development, including clear cell renal cell carcinoma (ccRCC). Herein, we first noticed that the expression levels of cuproptosis regulators exhibited a tight correlation with the clinicopathological characteristics of ccRCC. The cuproptosis-sensitive sub-type (CSS), classified via consensus clustering analysis, harbored a higher overall survival rate compared to the cuproptosis-resistant sub-type (CRS), which may have resulted from the differential infiltration of immune cells. FDX1, the cuproptosis master regulator, was experimentally determined as a tumor suppressor in ccRCC cells by suppressing the cell growth and cell invasion of ACHN and OSRC-2 cells in a cuproptosis-dependent and -independent manner. The results from IHC staining also demonstrated that FDX1 expression was negatively correlated with ccRCC tumor initiation and progression. Furthermore, we identified the miR-21-5p/FDX1 axis in ccRCC and experimentally verified that miR-21-5p directly binds the 3′-UTR of FDX1 to mediate its degradation. Consequently, a miR-21-5p inhibitor suppressed the cell growth and cell invasion of ACHN and OSRC-2 cells, which could be compensated by FDX1 knockdown, reinforcing the functional linkage between miR-21-5p and FDX1 in ccRCC. Finally, we evaluated the ccRCC tumor microenvironment under the miR-21-5p/FDX1 axis and noted that this axis was strongly associated with the infiltration of immune cells such as CD4+ T cells, Treg cells, and macrophages, suggesting that this signaling axis may alter microenvironmental components to drive ccRCC progression. Overall, this study constructed the miR-21-5p/FDX1 axis in ccRCC and analyzed its potential impact on the tumor microenvironment, providing valuable insights to improve current ccRCC management. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is the most common type of malignant tumor of the bile duct and is characterized by high morbidity and mortality; it is difficult to diagnose in the early stages and responds poorly to current conventional radiotherapy and chemotherapy. The present study investigated the role of GSK-3β signaling on the anticancer effects of doxorubicin in human CCA cells. Blocking GSK-3β enhanced the sensitivity of human CCA cells to doxorubicin (Dox)-induced apoptosis, which was accompanied by decreased AKT and focal adhesion kinase (FAK) activity. Moreover, inhibiting GSK-3β using 6-bromoindirubin-3′-oxime, CHIR99021 or small interfering RNA decreased phosphorylation of FAK and AKT, and promoted apoptosis of Dox-induced human CCA cells. Moreover, FAK inhibition suppressed AKT activity independently of phosphoinositide 3-kinase activity. These results indicated that GSK-3β protects human CCA cells against Dox-induced apoptosis via sustaining FAK/AKT activity. [ABSTRACT FROM AUTHOR]

Although activating transcription factor 4 (ATF4) is involved in the regulation of numerous biological functions, whether ATF4 has a direct role in liver injury is unknown. The aim of the present study was to investigate the role of ATF4 in liver injury using mouse models. The results revealed that ATF4 protein is expressed markedly higher in the mouse liver when in comparison with other tissues. Notably, tunicamycin treatment, an endoplasmic reticulum (ER) stress inducer, induced the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), but decreased ATF4 protein levels in the mouse liver. This suggested an unconventional regulation pattern of ATF4 protein not associated with ER stress or eIF2α. In addition, it was also observed that the liver levels of ATF4 protein were significantly reduced upon chronic liver injury induced by carbon tetrachloride (CCl4). ATF4 protein was also decreased in acute liver injury induced by lipopolysaccharide (LPS) plus D‑galactosamine (D‑GalN). Furthermore, the results revealed that knockdown of ATF4 by injecting ATF4‑targeting Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)‑CRISPR associated protein 9 plasmids exacerbated CCl4 and LPS/D‑GalN‑induced liver injury as demonstrated by elevated serum aspartate transaminase and alanine aminotransferase levels. ATF4 suppression also enhanced CCl4 and LPS/D‑GalN mediated c‑Jun N‑terminal kinase activation. By contrast, ATF4 overexpression alleviated CCl4 and LPS/D‑GalN‑induced liver injury. Taken together, these observations suggested that ATF4 may serve a protective role in the mouse liver. [ABSTRACT FROM AUTHOR]

The unfolded protein response (UPR) is a conserved adaptive response utilized by cells to cope with endoplasmic reticulum (ER) stress. In addition to the UPR, cells also trigger other adaptive responses under ER stress conditions. Although the PI3K/Akt and MEK/ERK pathways are known to protect cells from ER stress-induced apoptosis, their other functions under ER stress remain elusive. Here, we showed that long-term ER stress resulted in inactivation of Akt and activation of ERK in human hepatocellular carcinoma (HCC) cells. Importantly, both PI3K inhibitor LY294002 and dominant-negative Akt construct promoted tunicamycin- and thapsigargin-induced ERK phosphorylation. In addition, constitutively active Akt construct inhibited ER stress-induced ERK phosphorylation. We also showed that ER stress-induced PI3K/Akt inactivation contributed to cell cycle arrest and MEK/ERK inhibition moderately increased cell percentage in the S phase. It is notable that U0126 made HCC cells much more sensitive to ER stress-induced apoptosis than LY294002. Taken together, our results indicate that there is cross-talk between the PI3K/Akt and MEK/ERK cascades under ER stress in HCC cells, which contributes to both cell cycle arrest and cell survival. We propose that ER stress-induced cross-talk between the PI3K/Akt and MEK/ERK cascades is a protective mechanism utilized by HCC cells to adapt to stress.