Role of autophagy in cholangiocarcinoma: An autophagy-based treatment strategy

Abstract

Cholangiocarcinomas (CCAs) are diverse biliary epithelial tumours involving the intrahepatic, perihilar and distal parts of the biliary tree. The three entirely variable entities have distinct epidemiology, molecular characteristics, prognosis and strategy for clinical management. However, many cholangiocarcinoma tumor-cells appear to be resistant to current chemotherapeutic agents. The role of autophagy and the therapeutic value of autophagy-based therapy are largely unknown in CCA. The multistep nature of autophagy offers a plethora of regulation points, which are prone to be deregulated and cause different human diseases, including cancer. However, it offers multiple targetable points for designing novel therapeutic strategies. Tumor cells have evolved to use autophagy as an adaptive mechanism for survival under stressful conditions such as energy imbalance and hypoxic region of tumors within the tumor microenvironment, but also to increase invasiveness and resistance to chemotherapy. The purpose of this review is to summarize the current knowledge regarding the interplay between autophagy and cholangiocarcinogenesis, together with some preclinical studies with agents that modulate autophagy in order to induce tumor cell death. Altogether, a combinatorial strategy, which comprises the current anti-cancer agents and autophagy modulators, would represent a positive CCA patient approach.

The Implication of Autophagy in Gastric Cancer Progression

“…Some noteworthy rapalogs are everolimus, as well as temsirolimus, while deforolimus is a rapamycin analog, which activates the autophagy mechanism [84]. It is reported that the addition of Paclitaxel inEverolimus therapy has a significant suppressive effect on endometrial cancer cell progression [85]. There is a notable effect of Rapamycin as an anti-cancer treatment, which includes the activation of the autophagy pathway, the enhancement of radiationtherapy's effect on lung cancer cells of the -A549 type, and it also influences the DNA-repair process [86].…”

“…For breast malignancy, in the absence of mutant BRCA1 gene, metformin can be included in therapeutic schemes with spautin-1, which constitutes an autophagy suppressor, resulting in an altered mitochondrial functional state and inducing a notable reduction incancer cell survival and progression [88,90]. Furthermore, significant autophagy suppressors are mTOR inhibitors, such as alkaloids [90,91], including cepharanthine, liensinine, andisoliensinine [85], while they induce phosphorylation of the AMPK pathway. The above autophagy activators demonstrate great results in cases of resistant apoptosis in Mouse Embryonic Fibroblasts (MEFs) [92].…”

“…Another autophagy activator, a pan-inhibitor of anti-apoptotic Bcl-2 proteins that exhibits a cytotoxic effect on cancer cells through both apoptosis-dependent and -independent pathways, the socalled Obatoclax [93], is correlated with mitochondrial-pathway apoptosis via targeting the Bcl-2 protein family, and it is also linked with autophagy-complexes' death via necroptosis [88,92]. Last but not least, the antioxidant omega-3polyunsaturated fatty acids have a key role in autophagy activation [94], constitute a potent adjuvant anti-cancer agent, such as in case of cholangiocarcinoma, while they do not have notable toxicity [85]. These agents activate 15-hydroxyprostaglandin dehydrogenase, which leads to the suppression of prostaglandin E2 (PGE2), which is a causative factor for the above malignancy [88].…”

An Insight into the Novel Immunotherapy and Targeted Therapeutic Strategies for Hepatocellular Carcinoma and Cholangiocarcinoma

“…In western countries is closely associated with chronic inflammation of the biliary tract, such as primary sclerosing cholangitis (PSC), biliary lithiasis, metabolic diseases, as well as chronic hepatic inflammatory diseases, including viral hepatitis B and C, NASH, mainly for intrahepatic cholangiocarcinogenesis. In Eastern countries, two well-demonstrated risks factor is a parasitic infection with larvae of Opisthorchis viverrini, and Clonorchissinesis via food consumption, as well as exposure to aflatoxins [ 7 , 8 ], which is also associated with HCC development. There is a notable association of anatomical sub-entities including, FGFR gene fusions, mutant IDH1/2, ARID1A, and BRAF genes in intrahepatic CCAs (iCCAs), while for extrahepatic tumors mutations in ELF3, IDH1/2, as well as PRKACA/B and FGFER fusions, while, TP53 and KRAS mutations are also reported for both subtypes [ 9 , 10 ].…”

Iodine-125 induced cholangiocarcinoma cell death is enhanced by inhibition of endoplasmic reticulum stress-mediated protective autophagy

“…Studies have suggested autophagy plays an important role in the energy balance of cancer cells and may regulate the survival mechanism of cancer cells as a tumor promoter or tumor suppressor, and its intervention has become an effective strategy for cancer treatment [14,15]. Moreover, autophagy induction or autophagy inhibition has been used for the treatment of CCA in clinical studies, indicating that autophagy is an effective target for CCA therapy [16,17]. However, the molecular basis of the relationship between autophagy and I-125 seed radiation in CCA has not yet been further studied, to the best of our knowledge.…”