scholarly journals BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Stephanie Busche ◽  
Katharina John ◽  
Franziska Wandrer ◽  
Florian W. R. Vondran ◽  
Ulrich Lehmann ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Protein Expression ◽  
Immune Checkpoint Inhibitor ◽  
Kinase Inhibitors ◽  
Death Receptor ◽  
Mitochondrial Pathway ◽  
Alternative Treatment Option ◽  
Hcc Cells ◽  
Global Health Challenge

AbstractHepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.

scholarly journals A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma

2021 ◽  
Vol 11 (5) ◽  
pp. 332
Author(s):  
Szu-Jen Wang ◽  
Pei-Ming Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Cancer Genomics ◽  
Gene Signature ◽  
Migration And Invasion ◽  
Advanced Hcc ◽  
Telomerase Inhibitor ◽  
Cell Cycle Related Gene ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is a relatively chemo-resistant tumor. Several multi-kinase inhibitors have been approved for treating advanced HCC. However, most HCC patients are highly refractory to these drugs. Therefore, the development of more effective therapies for advanced HCC patients is urgently needed. Stathmin 1 (STMN1) is an oncoprotein that destabilizes microtubules and promotes cancer cell migration and invasion. In this study, cancer genomics data mining identified STMN1 as a prognosis biomarker and a therapeutic target for HCC. Co-expressed gene analysis indicated that STMN1 expression was positively associated with cell-cycle-related gene expression. Chemical sensitivity profiling of HCC cell lines suggested that High-STMN1-expressing HCC cells were the most sensitive to MST-312 (a telomerase inhibitor). Drug–gene connectivity mapping supported that MST-312 reversed the STMN1-co-expressed gene signature (especially BUB1B, MCM2/5/6, and TTK genes). In vitro experiments validated that MST-312 inhibited HCC cell viability and related protein expression (STMN1, BUB1B, and MCM5). In addition, overexpression of STMN1 enhanced the anticancer activity of MST-312 in HCC cells. Therefore, MST-312 can be used for treating STMN1-high expression HCC.

Arsenic Trioxide-Induced Cell Death Occurs Partially Independent of the Pro-Apoptotic Bcl-2-Family Members Bax and Bak.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4585-4585
Author(s):  
Christian Scholz ◽  
Antje Richter ◽  
Anja Richter ◽  
Bernd Dörken ◽  
Peter T. Daniel
Keyword(s):  
Cell Death ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Family Members ◽  
Death Receptor ◽  
Hematologic Malignancies ◽  
Mitochondrial Pathway ◽  
Cell Death Pathways

Abstract Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed for the treatment of acute promyelocytic leukaemia, myelodysplastic syndrome, and multiple myeloma. Investigating the mechanisms of arsenic trioxide-induced cell death, we recently demonstrated that arsenite-mediated cell demise has a partially necrotic phenotype, occurs independently of the extrinsic death receptor pathway of apoptosis, and is not hampered by the absence of functioning caspases. On the contrary, cell death proceeded entirely via an intrinsic, mitochondrial pathway and was efficiently blocked by the anti-apoptotic Bcl-2 family members Bcl-2 or Bcl-xL. Here, we address the role of the pro-apoptotic multi-domain Bcl-2 family members Bax and Bak. By employing different cell lines deficient for Bax and/or Bak, we demonstrate that Bax- or Bak-deficiency as well as the combined absence only partially blocks arsenite-induced cell death. While the detection of an additive effect of the combined Bax-/Bak-deficiency argues for a non redundant function of Bax and Bak, the persistence of a substantial percentage of arsenite-mediated cell demise in different double deficient cell lines nevertheless suggests a mode of arsenic trioxide-mediated cell death independent from these central inducers of apoptotic cell demise. The presented data add to the notion that arsenic trioxide kills tumor cells independent of the apoptotic machinery, and warrants further investigation on the efficacy of this compound in malignancies with deficiencies of the apoptotic cell death pathways.

scholarly journals Zingiberensis Newsaponin Inhibits the Malignant Progression of Hepatocellular Carcinoma via Suppressing Autophagy Moderated by the AKR1C1-Mediated JAK2/STAT3 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Keqing He ◽  
Xing Liu ◽  
Shiping Cheng ◽  
Pingsheng Zhou
Keyword(s):  
Oxidative Stress ◽  
Hepatocellular Carcinoma ◽  
Protein Expression ◽  
Cell Viability ◽  
Underlying Mechanism ◽  
Anticancer Effect ◽  
Stat3 Pathway ◽  
Stress Markers ◽  
And Migration ◽  
Hcc Cells

Objective. Saponins are a group of compounds from various plants, which exhibit an anticancer activity. This study aimed to explore the anticancer effect of zingiberensis newsaponin (ZnS) against hepatocellular carcinoma (HCC) and the underlying mechanism involving autophagy. Methods. HCC cells (Huh7 and SMMC7721) were treated with ZnS and/or 3-MA. The cell viability, migration, and apoptosis were determined using CCK-8 assay, transwell assay, and flow cytometry, respectively. The levels of oxidative stress markers (ROS, SOD, and MDA) were measured by ELISA assay. Autophagy was monitored using MDC assay, immunofluorescence staining, and transmission electron microscopy. The relative protein expression of LC3II/LC3I, P62, AKR1C1, p-JAK2, p-STAT3, JAK2, and STAT3 was determined using Western blot. Results. ZnS or 3-MA inhibited the cell viability and migration, and it promoted cell apoptosis and oxidative stress in HCC. MDC-positive cells and autophagosomes were reduced by ZnS or 3-MA treatment. The expression of autophagy-related proteins LC3 (LC3II/LC3I) and P62 was, respectively, downregulated and upregulated after ZnS or 3-MA treatment. In addition, ZnS or 3-MA suppressed the protein expression of AKR1C1, p-JAK2, and p-STAT3 in HCC cells. Furthermore, the above phenomena were evidently enhanced by ZnS combined 3-MA treatment. AKR1C1 overexpression weakened the effect of ZnS on inhibiting the expression of AKR1C1, p-JAK2, and p-STAT3. Conclusion. ZnS exerts an anticancer effect on HCC via inhibiting autophagy moderated by the AKR1C1-mediated JAK2/STAT3 pathway. ZnS and 3-MA exert a synergistic effect on inhibiting HCC.

scholarly journals A Case of Poorly Differentiated Hepatocellular Carcinoma, Lymphocyte-rich.

2021 ◽  
Author(s):  
Ginji Omori ◽  
Takahiro Osuga ◽  
Koji Miyanishi ◽  
Kota Hamaguchi ◽  
Shingo Tanaka ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Programmed Cell Death 1 ◽  
Poorly Differentiated ◽  
Inhibitor Treatment

A 70-year-old woman was diagnosed poorly differentiated hepatocellular carcinoma (HCC), lymphocyte rich. In this case, programmed cell death 1 expression was observed. Immune checkpoint inhibitor treatment may be effective in such cases, although there have been no reports of their use for poorly differentiated HCC, lymphocyte-rich.

scholarly journals Hypoxic hepatocellular carcinoma cells acquire arsenic trioxide resistance through upregulating HIF-1α expression

2020 ◽  
Author(s):  
Yaoting Chen ◽  
Huiqing Li ◽  
Dong Chen ◽  
Xiongying Jiang ◽  
Weidong Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Protein Expression ◽  
Arsenic Trioxide ◽  
Therapeutic Effects ◽  
Advanced Hepatocellular Carcinoma ◽  
Antitumor Effects ◽  
P Glycoprotein ◽  
Hcc Cells

Abstract Background : Although arsenic trioxide (ATO) is used in the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials, it is not satisfactory in terms of improving HCC patients’ overall survival. Intratumoral hypoxia and overexpression of hypoxia-inducible-1α (HIF-1α) may result in ATO-resistance and tumor progression. We investigated the mechanisms involving HIF-1α expression and acquired ATO chemoresistance in HCC cells and mice. Methods: The therapeutic effects of ATO in normoxic and hypoxic HCC cells were assessed using cell viability and apoptosis assays in vitro and a xenograft model in vivo . mRNA and protein expression of HIF-1α, P-glycoprotein, and VEGF were measured by qRT-PCR and western blotting. HIF-1α inhibition was performed to investigate the mechanism of ATO-resistance. VEGF secretion was tested using ELISA and tube-formation assays. Results : Compared to normoxic cells, hypoxic HCC cells were more resistant to ATO, with higher IC 50 values and less apoptosis, and upregulated HIF-1α protein expression, accompanied with the enhancement of P-glycoprotein and VEGF synthesis after ATO treatment. VEGF secretion was elevated in the supernatant of ATO-treated HCC cells, and this change can potentiate angiogenesis in vitro . HIF-1α inhibition attenuated ATO-resistance and angiogenesis, and promoted the anticancer effects of ATO both in vitro and in vivo by downregulating therapy-induced P-glycoprotein and VEGF overexpression. Conclusions : Hypoxic HCC cells acquire ATO resistance by upregulating HIF-1α levels; thus, combining ATO with a HIF-1α-targeting agent may lead to enhanced antitumor effects in HCC.

scholarly journals Hepatocyte Death: A Clear and Present Danger

2010 ◽  
Vol 90 (3) ◽  
pp. 1165-1194 ◽  
Author(s):  
Harmeet Malhi ◽  
Maria Eugenia Guicciardi ◽  
Gregory J. Gores
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Enterohepatic Circulation ◽  
Tissue Injury ◽  
Death Receptor ◽  
Mitochondrial Pathway ◽  
Hepatocyte Injury ◽  
The Unfolded Protein Response

The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, the widespread prevalence of hepatotropic viruses, and its existence within a milieu of innate immune responding cells. Apoptosis and necrosis are the most widely recognized forms of hepatocyte cell death. The hepatocyte displays many unique features regarding cell death by apoptosis. It is quite susceptible to death receptor-mediated injury, and its death receptor signaling pathways involve the mitochondrial pathway for efficient cell killing. Also, death receptors can trigger lysosomal disruption in hepatocytes which further promote cell and tissue injury. Interestingly, hepatocytes are protected from cell death by only two anti-apoptotic proteins, Bcl-xL and Mcl-1, which have nonredundant functions. Endoplasmic reticulum stress or the unfolded protein response contributes to hepatocyte cell death during alterations of lipid and fatty acid metabolism. Finally, the current information implicating RIP kinases in necrosis provides an approach to more fully address this mode of cell death in hepatocyte injury. All of these processes contributing to hepatocyte injury are discussed in the context of potential therapeutic strategies.

Silencing non-SMC chromosome-associated polypeptide G inhibits proliferation and induces apoptosis in hepatocellular carcinoma cells

2018 ◽  
Vol 96 (12) ◽  
pp. 1246-1254 ◽  
Author(s):  
Kaikun Liu ◽  
Yumin Li ◽  
Bo Yu ◽  
Furong Wang ◽  
Taiyu Mi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Liver Cancer ◽  
Protein Expression ◽  
Mrna Expression ◽  
Mrna Level ◽  
A Subunit ◽  
Underlying Mechanisms ◽  
Colony Forming Capacity ◽  
Hcc Cells

The present study was designed to investigate the significance of non–structural maintenance of chromosomes (non-SMC) chromosome-associated polypeptide G (NCAPG), a subunit of condensin complex I, in the development of hepatocellular carcinoma (HCC). NCAPG protein expression in human HCC and paracancerous hepatic tissues were examined using immunohistochemistry, and NCAPG mRNA expression in HCC cell lines were quantified using quantitative RT–PCR. Lentivirus-mediated RNA interference was used to silence NCAPG in HCC cells. Cell proliferation was monitored by MTT assay. Cell colony-forming capacity was measured by colony formation assay. Apoptosis was determined by flow cytometry. The results showed that increased protein expression of NCAPG was found in HCC tissues compared with the matched paracancerous hepatic tissues. At the mRNA level, increased expression of NCAPG was found in HCC cells as opposed to the normal hepatocytes. Silencing of NCAPG in BEL-7404 and SMMC-7721 cells led to decreased cell proliferation and increased apoptosis. These changes were associated with increased mRNA expressions of P53, P27, and Bad, but decreased mRNA expression of EGFR, Akt, survivin, and JNK. NCAPG might play an oncogenic role in the development of liver cancer. Further studies to clarify its role and underlying mechanisms in the development of liver cancer are warranted.

scholarly journals Fermented Wheat Germ Extract Induced Cell Death and Enhanced Cytotoxicity of Cisplatin and 5-Fluorouracil on Human Hepatocellular Carcinoma Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Cheng-Jeng Tai ◽  
Wen-Ching Wang ◽  
Chien-Kai Wang ◽  
Chih-Hsiung Wu ◽  
Mei-Due Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Wheat Germ ◽  
Adenosine Diphosphate ◽  
Chemotherapeutic Agents ◽  
Current Therapy ◽  
Wheat Germ Extract ◽  
Combination Drug ◽  
Fermented Wheat Germ Extract ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Due to the difficulties of early diagnosis, curative treatments are not available for most patients. Palliative treatments such as chemotherapy are often associated with low response rate, strong adverse effects and limited clinical benefits for patients. The alternative approaches such as fermented wheat germ extract (FWGE) with anti-tumor efficacy may provide improvements in the clinical outcome of current therapy for HCC. This study aimed to clarify antitumor efficacy of FWGE and the combination drug effect of FWGE with chemotherapeutic agents, cisplatin and 5-fluorouracil (5-Fu) in human HCC cells, HepG2, Hep3B, and HepJ5. The present study indicated that FWGE exhibited potential to suppress HepG2, Hep3B, and HepJ5 cells, with the half maximal inhibitory concentrations (IC50) of FWGE were 0.494, 0.371 and 1.524 mg/mL, respectively. FWGE also induced Poly (Adenosine diphosphate ribose) polymerase (PARP) associated cell death in Hep3B cells. Moreover, the FWGE treatment further enhanced the cytotoxicity of cisplatin in all tested HCC cells, and cytotoxicity of 5-Fu in a synergistic manner in HepJ5 cells. Collectively, the results identified the anti-tumor efficacy of FWGE in HCC cells and suggested that FWGE can be used as a supplement to effectively improve the tumor suppression efficiency of cisplatin and 5-Fu in HCC cells.

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