A Comprehensive Review on PCSK9 as Mechanistic Target Approach in Cancer Therapy

Abstract

: PCSK9 is a strongly expressed protein in the liver and brain that binds to the LDLR and regulates cholesterol in the liver effectively. Other receptors with which it interacts include VLDLR, LRP1, ApoER2, and OLR1. PCSK9 gain-of-function results in lysosomal degradation of these receptors, which may result in hyperlipidemia. PCSK9 deficiency results in a lower amount of cholesterol, which reduces cholesterol's accessibility to cancer cells. PCSK9 regulates several proteins and signaling pathways in cancer, including JNK, NF-κВ, and the mitochondrial-mediated apoptotic pathway. In the liver, breast, lungs, and colon tissue, PCSK9 initiates and facilitates cancer development, while in prostate cancer cells, it induces apoptosis. PCSK9 has a significant impact on brain cancer, promoting cancer cell survival by manipulating the mitochondrial apoptotic pathway and exhibiting apoptotic activity in neurons by influencing the NF-κВ, JNK, and caspase-dependent pathways. The PCSK9 impact in cancer at different organs is explored in this study, as well as the targeted signaling mechanisms involved in cancer growth. As a result, these signaling mechanisms may be aimed for the development and exploration of anti-cancer drugs in the immediate future.

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

“…It has been observed that the inhibition or deficiency of PCSK9 can yield therapeutic benefits in cancer treatment, by not only curbing tumorigenesis but also enhancing anti-tumor immunity. 440 , 441 Encouragingly, several therapeutic strategies designed to directly inhibit PCSK9 have already been rigorously explored in the context of hyperlipidemia management. This rigorous investigation resulted in the approval of three mAbs and one siRNA agent that can obstruct both intracellular and extracellular PCSK9 function.…”

“…This rigorous investigation resulted in the approval of three mAbs and one siRNA agent that can obstruct both intracellular and extracellular PCSK9 function. 441 In this segment, we consolidate the existing approaches developed to inhibit PCSK9 in the context of cancer treatment.…”

Association between Immune Checkpoint Inhibitors and Atherosclerotic Cardiovascular Disease Risk: Another Brick in the Wall

“…Preclinical studies in mice with melanoma also suggested that silencing the PCSK9 gene significantly enhanced the response to ICIs [ 90 , 91 ]. Notably, PCSK9 is not only expressed by cancer cells but is also released by them [ 92 , 93 ]. A study in NSCLC patients showed that low systemic levels of PCSK9 (<95 ng/mL) predict a more favorable response to the PD-1 inhibitor Nivolumab and are associated with improved OS compared to patients with higher levels (>120 ng/mL) [ 94 ].…”