Chloroquine affects autophagy to achieve an anticancer effect in EC109 esophageal carcinoma cells in�vitro

Abstract

Abstract. Esophageal carcinoma is a malignancy that severely threatens human health, with a high incidence rate and a low 5-year survival rate. Resistance to chemotherapy frequently emerges during its treatment, partly due to the induction of autophagy. Therefore, targeting autophagy may be a promising therapeutic approach for the treatment of esophageal carcinoma. In the present study, it was investigated how chloroquine (CQ) can influence the growth ability and biological behaviors of EC109 esophageal squamous carcinoma cells in vitro, as well as the potential molecular mechanisms behind its activity. It was demonstrated that CQ could suppress the growth and proliferation of EC109 cells in a time-and dose-dependent manner; migration and colony formation abilities were also inhibited by CQ. Furthermore, subsequent to the exposure to CQ, the number of autophagosomes was clearly increased in EC109 cells overexpressing green fluorescent protein tagged-light chain (LC)3 when observed by fluorescence microscopy. Protein expression of the endogenous autophagy markers LC3-II and p62 was elevated subsequent to CQ treatment, whereas the expression of proteins from the protein kinase B/mechanistic target of rapamycin target of rapamycin pathway was inhibited. This suggested that CQ could induce the formation of autophagosomes in the initiation of autophagy, but inhibit the degradation of autophagosomes in a later stage of autophagy. The overall effect was that autophagic cell death was activated by CQ, as confirmed by flow cytometry. Overall, the anticancer effect of chloroquine on EC109 was revealed to be mediated through modulating autophagy, and this may produce promising therapeutic benefits for esophageal carcinoma.

Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies

“…Although several clinical trials showed the benefits of chloroquine as an anti-tumor drug ( 308 ), the precise molecular mechanisms of chloroquine-mediated effects has not been established. It was proposed that chloroquine may influence autophagy ( 309 ). Chloroquine in combination with other chemotherapeutic drugs could increase the efficiency of drug treatment, although it can accelerate chemotherapy-associated organ injury ( 301 ).…”

Differences in Cellular Clearing Mechanisms of Aggregates of Two Subtypes of HLA-B27

“…During the initiation of autophagy, LC3-I is cleaved and lipidated to form LC3-II; p62 is another autophagy marker, which is sequestered within autophagosomes, followed by degradation by lysosomes ( 37 ). Treatment with CQ induces the formation of autophagosomes, with inhibition of autophagosome degradation in the later stage of autophagy ( 38 ). The decrease in HC10-specific forms of B*2704 observed in the presence of CQ may be justified on the basis of the fact that although CQ treatment inhibits autophagy, it can induce ER stress as well as UPR through the PERK-eIF2α-ATF4 pathway ( 39 ), so that the clearance of aggregated forms of the protein may be UPR-driven.…”

Therapeutic Approach of KRAS Mutant Tumours by the Combination of Pharmacologic Ascorbate and Chloroquine

“…Physiological conditions refer to those conditions which occur in nature for the cellular system and no inner or outer stress is induced. The parameters values were perturbed to capture all the possible qualitative behaviours that the given network can exhibit (e.g., with the addition of ascorbate, the inactivation rate of KRAS was increased; in cases of chloroquine treatment, the inactivation rate of mTOR was induced) and the level of autophagy was decreased [ 49 , 50 ].…”