Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway

Abstract

Background PCSK9 has been found to be closely related to the occurrence and development of a variety of tumors. However, the concrete role of PCSK9 and its relationship with HCC development is largely unknown. Methods The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry assays. The effects of PCSK9 expression on HCC biological traits were investigated by overexpressing and downregulating PCSK9 protein in vivo and in vitro. The mechanism by which PCSK9 mediates the depolymerization of the GSTP1 dimer and the phosphorylation of the JNK signaling pathway was further investigated. Results PCSK9 is downregulated in human HCC tissues. HCC cell proliferation, cell cycle phase distribution and apoptosis were inhibited by PCSK9 in vitro. PCSK9 suppresses tumor growth and metastasis of HCC in vivo. PCSK9 interacts with GSTP1 and promotes the depolymerization of the GSTP1 dimer and inactivation of the JNK signaling pathway. Furthermore, low PCSK9 protein expression in primary HCC tissues correlated with worse clinical outcomes. Conclusions PCSK9 inhibits HCC cell proliferation, cell cycle phase distribution and apoptosis by interacting with GSTP1 and suppressing the JNK signaling pathway, suggesting that PCSK9 might act as a tumor suppressor and may serve as a therapeutic target for the treatment of HCC.

Glutathione S-Transferases S1, Z1 and A1 Serve as Prognostic Factors in Glioblastoma and Promote Drug Resistance through Antioxidant Pathways

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Angiogenesis in hepatocellular carcinoma: mechanisms and anti-angiogenic therapies

“…First, current anti-angiogenic clinical trials induce only a modest improvement in OS, measurable in just several months. Given that HCC has multiple pathways for recruiting vessels, blocking one target alone may have incomplete effects on tumor angiogenesis, because the tumor cells may switch from one mechanism to another 132,138 . However, the use of anti-angiogenic molecules may lead to a hypoxic TME, which alters the cell phenotype and enhances tumor invasiveness, whereas the tumor-infiltrating cells, including TAMs, TANs, and TAFs, may decrease the response to anti-angiogenic therapies 139 .…”

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“…46 On the contrary, other studies reported decreased PCSK9 expression in HCC implying that liver tumors can modulate their local and adjacent microenvironment, thus enabling energy supply to fuel tumor growth. 47 A brilliant study demonstrated that deleting PCSK9 gene in rodent cancer cells substantially affects their growth in vivo and, notably, improves the efficacy of anti-programmed cell death protein 1 (PD1) therapy, opening the way towards combined immune checkpoint-based strategies. Mechanisms of action seem independent of the cholesterol regulation, rather relying on the recycling of MHC I molecules for degradation to lysosomes.…”