Current Issues in Molecular Biology

Special Issue Editors

Dr. Bor-Chyuan Su

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Guest Editor

Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
Interests: cell death; signal transduction; cancer biology

Dr. Hsin-Hsien Yu

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Guest Editor

Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 110, Taiwan
Interests: surgical oncology; gastric cancer research; peritoneal surface malignancy; cytoreductive surgery and hyperthermic intraperitoneal chemotherapy; laparoscopic and robotic digestive surgery
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Dear Colleagues,

The main approach to cancer treatment is to specifically cause death in tumor cells. This aim can be met by inducing any of the three major forms of cell death, including apoptosis, autophagy, and necrosis, via distinct molecular mechanisms. Although the induction of any form of cell death can be effective as an anticancer strategy, the roles of each pathway in cancer therapy are complex and often context dependent. In addition, it is not uncommon for cancer cells to develop resistance to therapy-induced cell death. Thus, a deep understanding of how cancer therapeutics affect the regulatory pathways of cell death will allow researchers to develop more precise and effective anticancer strategies.

For this Special Issue, appropriate research topics include cancer cell death regulation, novel therapeutic targets, molecular mechanisms, and drug (therapy) resistance.

Dr. Bor-Chyuan Su
Dr. Hsin-Hsien Yu
Guest Editors

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Keywords

cell death
anti-cancer agents
signal transduction
chemoresistance
therapeutic resistance
apoptosis
autophagy
necrosis

Published Papers (2 papers)

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Research

19 pages, 4810 KiB

Open AccessArticle

The Identification of New c-FLIP Inhibitors for Restoring Apoptosis in TRAIL-Resistant Cancer Cells

by Katherine Yaacoub, Rémy Pedeux, Pierre Lafite, Ulrich Jarry, Samia Aci-Sèche, Pascal Bonnet, Richard Daniellou and Thierry Guillaudeux

Curr. Issues Mol. Biol. 2024, 46(1), 710-728; https://doi.org/10.3390/cimb46010046 - 12 Jan 2024

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Abstract

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following death receptors’ (DRs) activation via the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. The inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These molecules selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these nine molecules using the human lung cancer cell line H1703, overexpressing c-FLIP. Our results showed that six of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC immunoprecipitation assay. The overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis; however, a combination of TRAIL with these selected molecules significantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical molecules efficiently prevent c-FLIP recruitment into the DISC complex, thus restoring the caspase-8-dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory molecules that may serve as anticancer agents in tumors overexpressing c-FLIP. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cancer Cell Death)

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14 pages, 3798 KiB

Open AccessArticle

Cucurbitacin E Exerts Anti-Proliferative Activity via Promoting p62-Dependent Apoptosis in Human Non-Small-Cell Lung Cancer A549 Cells

by Han-Lin Hsu, Bo-Jyun Lin, Yu-Chen Lin, Chih-Chieh Tu, Nham-Linh Nguyen, Ching-Chiung Wang, Mei-Chuan Chen and Chun-Han Chen

Curr. Issues Mol. Biol. 2023, 45(10), 8138-8151; https://doi.org/10.3390/cimb45100514 - 7 Oct 2023

Cited by 1 | Viewed by 1187

Abstract

EGFR tyrosine kinase inhibitors (TKIs) are the first-line treatment for advanced EGFR-mutated non-small-cell lung cancer (NSCLC). However, NSCLC patients with wild-type EGFR and KRAS mutation are ineligible for EGFR-TKIs. Therefore, the discovery of new therapeutic agents is urgently needed for NSCLC patients who cannot receive targeted therapies. Natural products possess tremendous chemical diversity and have been extensively investigated for their anticancer activity. In this study, we found that Cucurbitacin E (Cu E), a triterpene of cucurbitacins widely presented in the edible plants of the Cucurbitaceae family, significantly inhibits the viability and proliferation of A549 cells that harbor wild-type EGFR and KRAS mutation. Our results revealed that Cu E increases cell-cycle arrest at G2/M and subG1 phase. Mechanistically, Cu E significantly inhibits the phosphorylation and protein levels of regulatory proteins and hinders G2/M cell-cycle progression. Meanwhile, the treatment of Cu E resulted in DNA damage response and apoptosis. For the first time, we observed that Cu E induces incomplete autophagy as evidenced by increased LC3B-II expression and p62-accumulation. Knockdown of p62 rescued the cells from Cu E-mediated anti-proliferative effect, apoptosis, DNA damage, and ROS production. These findings suggest that Cu E is a promising drug candidate for NSCLC. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Cancer Cell Death)

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