Programmed Cell Death Pathways in Cholangiocarcinoma: Opportunities for Targeted Therapy

Abstract

Cholangiocarcinoma is a highly aggressive cancer arising from the bile ducts. The limited effectiveness of conventional therapies has prompted the search for new approaches to target this disease. Recent evidence suggests that distinct programmed cell death mechanisms, namely, apoptosis, ferroptosis, pyroptosis and necroptosis, play a critical role in the development and progression of cholangiocarcinoma. This review aims to summarize the current knowledge on the role of programmed cell death in cholangiocarcinoma and its potential implications for the development of novel therapies. Several studies have shown that the dysregulation of apoptotic signaling pathways contributes to cholangiocarcinoma tumorigenesis and resistance to treatment. Similarly, ferroptosis, pyroptosis and necroptosis, which are pro-inflammatory forms of cell death, have been implicated in promoting immune cell recruitment and activation, thus enhancing the antitumor immune response. Moreover, recent studies have suggested that targeting cell death pathways could sensitize cholangiocarcinoma cells to chemotherapy and immunotherapy. In conclusion, programmed cell death represents a relevant molecular mechanism of pathogenesis in cholangiocarcinoma, and further research is needed to fully elucidate the underlying details and possibly identify therapeutic strategies.

Keywords: apoptosis; cholangiocarcinoma; ferroptosis; necroptosis; programmed cell death; pyroptosis; targeted therapy.

Figure 1

The scheme highlights the main molecular pathways of apoptosis in CCA. The depicted pathways highlight the intricate interplay of various molecules, including pro-apoptotic proteins such as Bax and Bak, anti-apoptotic proteins like Bcl-2 and Bcl-xL, caspases, and FAS. FAS, a cell surface receptor, initiates the extrinsic pathway of apoptosis upon binding with its ligand, FASL. Image created with the support of Biorender.com (url https://www.biorender.com/).

Figure 2

The scheme highlights the main molecular pathways of ferroptosis in CCA. The depicted pathways highlight the crucial molecular players, including lipid peroxidation, glutathione metabolism, iron metabolism, redox homeostasis, and the involvement of Erastin, ALOX5, and BNIPe. Erastin inhibits the cysteine–glutamate transporter system, leading to glutathione depletion and increased susceptibility to ferroptosis. ALOX5, an enzyme involved in the synthesis of lipid mediators, promotes lipid peroxidation and contributes to ferroptosis. BNIPe, a member of the Bcl-2 family, induces mitochondrial dysfunction and enhances susceptibility to ferroptosis. Understanding these molecular mechanisms, including the roles of Erastin, ALOX5, and BNIPe, is crucial for developing targeted therapeutic strategies to induce ferroptosis in CCA, offering a potential avenue for cancer treatment. Image was created with the support of Biorender.com (https://www.biorender.com/).

Figure 3

The scheme highlights the main molecular pathways of pyroptosis in CCA. The depicted pathways highlight the intricate interplay of various molecules, including inflammasomes, caspases, gasdermin proteins (GSDMD), and pro-inflammatory cytokines such as IL-1β. Inflammasomes, multiprotein complexes, serve as sensors of cellular stress and activate caspases, particularly caspase-4/5/11, initiating pyroptosis. Gasdermin proteins are responsible for forming pores in the the cell membrane, leading to cell swelling and the release of pro-inflammatory cytokines. Understanding these molecular mechanisms is essential for developing targeted therapies to induce pyroptosis in CCA, potentially offering a novel approach for cancer treatment with implications for inflammation-associated diseases. Image created with the support of Biorender.com (https://www.biorender.com/).

Figure 4

The scheme highlights the main molecular pathways of necroptosis in CCA. The depicted pathways highlight the intricate interplay of various molecules, including receptor-interacting protein kinases (RIPKs), mixed lineage kinase domain-like protein (MLKL), and downstream effector proteins. In necroptosis, the activation of RIPKs, particularly RIPK1 and RIPK3, triggers the formation of a necrosome complex, leading to MLKL phosphorylation and subsequent membrane rupture. The release of intracellular contents stimulates an inflammatory response. Understanding these molecular mechanisms is essential for developing targeted therapies to induce necroptosis in CCA, potentially offering a novel strategy for cancer treatment with implications for modulating cell death pathways. Image created with the support of Biorender.com (url https://www.biorender.com/).