Proprotein convertase subtilisin/kexin Type 9 is required for Ahnak-mediated metastasis of melanoma into lung epithelial cells

Abstract

Highlights Ahnak −/− mice were more resistant to the pulmonary metastasis of B16F10 cells. Transcriptomic analyses revealed that PCSK9 was a candidate for lung metastasis. The lung metastasis was suppressed in Scgb1a1-Cre/PCSK9 fl/fl mice. Ahnak-TGFβ-PCSK9 axis regulates pulmonary metastasis of B16F10 cells.

Genetically proxied PCSK9 inhibition provides indication of lower prostate cancer risk: a Mendelian randomization study

“…PCSK9 is known as a regulator of the metabolism of LDL-c, although thus far its role in cancer susceptibility has yet to be comprehensively evaluated and characterized. There are various pre-clinical studies based on tumour tissue or mouse models which report the direct effects of PCSK9 or PCSK9 inhibitors on multiple types of cancer [50], including hepatocellular carcinoma [51,52], lung carcinoma [53,54], colorectal cancer [55] and breast cancer [56]. Additionally, Liu et al inoculated Pcsk9 knockout mouse cancer cells into syngeneic mouse hosts and observed delayed tumour growth, as well as a synergistic effect between PCSK9 inhibition and anti-PD1 antibody treatment to promote the efficacy of tumour growth suppression [57].…”

“…PCSK9 is known as a regulator of the metabolism of LDL-c, although thus far its role in cancer susceptibility has yet to be comprehensively evaluated and characterized. There are various pre-clinical studies based on tumour tissue or mouse models which report the direct effects of PCSK9 or PCSK9 inhibitors on multiple types of cancer [50], including hepatocellular carcinoma [51, 52], lung carcinoma [53, 54], colorectal cancer [55] and breast cancer [56]. Additionally, Liu et al .…”

The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer

“…While the physiological functions of PCSK9 in tissues other than liver ( 143 , 144 ), such as small intestine ( 145 , 146 ) and pancreatic β-cells ( 47 , 147 ), are starting to be defined, those in kidney, thymus, brain, and testis ( 41 ) still require more investigations. Tissue-specific PCSK9 KO in mouse small intestine ( 146 ), pancreatic β-cells ( 47 ), and lung epithelia ( 128 ) allowed some dissection of the relationship between the autocrine and endocrine functions of PCSK9 but clearly emphasized the dominant role of circulating PCSK9 originating from liver ( 48 , 80 ). Furthermore, the intracellular activity of PCSK9 found in cell lines ( 73 ) seems distinct from that of circulating PCSK9 ( 148 , 149 ) and may play important roles during embryonic development ( 41 ) and in placenta ( 85 , 150 ), and possibly explain the GOF of some PCSK9 variants.…”

“…Cholesterol plays a key role in a plethora of cellular metabolic processes, particularly for highly demanding anabolic steps such as cell growth and division, which are especially relevant to tumor growth and metastasis ( 126 ). Indeed, it was reported that PCSK9 deficiency reduces melanoma metastasis in liver ( 127 ), and that PCSK9 enhances metastasis of melanoma-derived cells into lung epithelial cells ( 128 ). The roles of PCSK9 in cancer have also been highlighted in terms of regulation of inflammation via a suppressor of cytokine signaling-3-signal transducer and activator of transcription 3 pathway ( 129 ), as well as of cell proliferation and apoptosis ( 130 ).…”

Circulating Levels of PCSK9, ANGPTL3 and Lp(a) in Stage III Breast Cancers

“…A recent study by Suh et al showed that nucleoprotein Ahnak mediated B16F10 melanoma cells mestatasis in mice via enhanced PCSK9 expression [74]. Actual data tend to support a pathogenic and pro-tumoral role for PCSK9, by both maintaining cholesterol supplies and by promoting MHC-I degradation on tumor cells, favoring immune escape of tumors [32].…”