Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma.
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ABSTRACT:
SUBMITTER: Sun EJ
PROVIDER: S-EPMC8615614 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer death in women worldwide. Although early diagnosis and cancer growth inhibition has significantly improved breast cancer survival rate over the years, there is a current need to develop more effective systemic treatments to prevent metastasis. One of the most commonly altered pathways driving breast cancer cell growth, survival, and motility is the PI3K/AKT/mTOR signaling cascade. In the past 30 years, a great surge of inhibitors targeting these key players has been developed at a rapid pace, leading to effective preclinical studies for cancer therapeutics. However, the central role of PI3K/AKT/mTOR signaling varies among diverse biological processes, suggesting the need for more specific and sophisticated strategies for their use in cancer therapy. In this review, we provide a perspective on the role of the PI3K signaling pathway and the most recently developed PI3K-targeting breast cancer therapies.
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Project description:BackgroundHepatocellular carcinoma (HCC) is the most common pathological type of liver cancer. Valosin-containing protein (VCP) is a member of the AAA-ATPase family associated with multiple molecular functions and involved in tumor metastasis and prognosis. However, the role of VCP in HCC progression is still unclear.MethodsWe examined the expression of VCP in HCC using the RNA sequencing and microarray data from public databases and measured it in clinical samples and cell lines by western blot, and immunohistochemistry (IHC). We also evaluated the correlation between VCP and clinical features. The VCP-interacting proteins were identified by co-immunoprecipitation combined with mass spectrometry (CoIP/MS). The underlying molecular mechanisms were investigated using in vitro and in vivo models of HCC.ResultsWe found that VCP expression is significantly increased in tumor tissues and is associated with advanced TNM stages and poorer prognosis in HCC patients. In vitro analyses revealed that VCP overexpression promoted HCC cell proliferation, migration, and invasion via PI3K/AKT/mTOR pathway activation. Conversely, VCP knockdown resulted in the reverse phenotypes. In vivo studies indicated that up-regulated VCP expression accelerated tumor growth in a subcutaneous HCC model. The D1 domain of VCP and A box of HMGB1 were identified as the critical regions for their interaction, and D1 area was required for the tumor-promoting effects induced by VCP expression. VCP enhanced the protein stability of HMGB1 by decreasing its degradation via ubiquitin-proteasome process. Inhibition of HMGB1 markedly attenuated VCP-mediated HCC progression and downstream activation of PI3K/AKT/mTOR signals.ConclusionCollectively, these findings demonstrate that VCP is a potential prognostic biomarker in HCC and exhibits oncogenic roles via PI3K/AKT/mTOR pathway activation. HMGB1 played an essential role in VCP-mediated HCC progression, indicating that VCP and HMGB1 are potential therapeutic targets in human HCC.
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Project description:Tenacissoside H (TEH), which has anti-inflammatory and anti-tumor effects, is a major active ingredient extracted from the stem of Marsdenia tenacissima. However, the effect of TEH on hepatocellular carcinoma (HCC) as well as the underlying mechanisms are still indistinct. Presently, HCC cells (including Huh-7 and HepG2) were dealt with different concentrations of TEH. The proliferation and apoptosis of HCC cells were determined via Cell Counting Kit-8 (CCK8) assay and flow cytometry. In addition, Western blot was conducted to evaluate the expressions of autophagy-and apoptosis-related proteins. Tissue immunofluorescence was carried out to evaluate LC3B expression in the tumor tissues. The data showed that TEH suppressed the growth of HCC cells in a concentration-dependent manner. Besides, TEH enhanced radiosensitivity and promoted the apoptosis of HCC cells. Moreover, the mRNA and protein levels of autophagy-related genes (LC3-II/LC2-I, ATG5, Beclin-1) were significantly promoted by TEH. Mechanistically, TEH attenuated the activation of PI3K/Akt/mTOR signaling pathway. However, inhibition of PI3 K pathway abolished the anti-tumor effects of TEH in HCC cells. Collectively, this study suggested that TEH increases the radiosensitivity of HCC cells via inducing autophagy and apoptosis through downregulating PI3K/Akt/mTOR signaling pathway.
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