Molecular Mechanisms to Target Cellular Senescence in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death and is the most common type of liver cancer. Due to the current paucity of drugs for HCC therapy there is a pressing need to develop new therapeutic concepts. In recent years, the role of Serum Response Factor (SRF) and its coactivators, Myocardin-Related Transcription Factors A and B (MRTF-A and -B), in HCC formation and progression has received considerable attention. Targeting MRTFs results in HCC growth arrest provoked by oncogene-induced senescence. The induction of senescence acts as a tumor-suppressive mechanism and therefore gains consideration for pharmacological interventions in cancer therapy. In this article, we describe the key features and the functional role of senescence in light of the development of novel drug targets for HCC therapy with a focus on MRTFs.

MRTF-A-NF-κB/p65 axis-mediated PDL1 transcription and expression contributes to immune evasion of non-small-cell lung cancer via TGF-β

“…Furthermore, our data identify that the multiple noncanonical pathways downstream of TGF-β cooperatively induce the expression, activation, nuclear translocation, and interaction of MRTF-A and its interaction with p65, thereby promoting the transcription and expression of PD-L1 and ultimately assisting the immune escape of certain cancer cells. Our findings are likely to have a significant impact on research on tumors in immunotherapy, since targeting the MRTF-A/p65 axis may be a promising strategy to enhance the efficacy of checkpoint immunotherapy against lung cancer and other types of cancers 42 .…”

“…PD-L1, TGF-β, and MRTF-A engage in extensive cross-talk in the occurrence of EMT 26 , 41 , 42 , and MRTF-A, as a transcriptional coactivator, is employed to regulate the transcription and translation of multiple genes. Therefore, we aimed to characterize whether MRTF-A participates in TGF-β-promoted transcription and expression of PD-L1.…”

Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective

“…Overall, the idea of senescent cells eventually being cleared by the immune system leads to application of pro-senescence therapy [ 39 , 93 ]. This is also supported by the fact that oncogene-induced senescence is a natural mechanism against tumor growth [ 17 , 18 ]. However, over-accumulation of senescent cells may instead have detrimental effects.…”

“…These are generally stress-related and include: genotoxic drugs (e.g., chemotherapy), irradiation, oncogene activation, cytokines (TGF-β), epigenetic modifiers (e.g., Curcumin), high-fat diets and ribosomal stress [ 15 ]. Oncogene-induced senescence (OIS) is possibly an important initial barrier against HCC occurrence [ 17 ]. OIS describes the “reflexive” induction of senescence in cells that receive excessive oncogenic stimuli, which subsequently protects against the uncontrolled proliferation of damaged cells [ 18 ].…”

“…It is generally suggested that a combination of pro-senescence therapy to halt tumor growth, with anti-senescence therapy to clear the senescent cells may be an effective senotherapeutic treatment approach [ 17 ]. In line with this hypothesis, Wang et al attempted to first use XL413 (a potent inhibitor of the DNA replication kinase CDC7) to induce senescence in malignant hepatocytes with mutations in TP53.…”