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- Title
Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy.
- Authors
Kim, Ryungsa; Kin, Takanori; Beck, William T.
- Abstract
Simple Summary: We summarize the current knowledge of the signaling pathways involved in anticancer drug-induced cell death. We discuss the common signaling pathways of apoptotic cell death, antiapoptotic pathways, non-apoptotic cell death mechanisms (autophagic, necrotic, and other), signaling pathways involved in the death of drug-sensitive and -resistant tumor cells (with emphasis on c-Jun/activator protein 1 and crosstalk with mitochondrial and endoplasmic reticulum pathways), and therapeutic implications of the modification of signaling pathways leading to cell death (with emphasis on cell death-related gene targeting, interactions of drug resistance factors in drug-resistant cells, and the unfolded protein response pathway). We provide suggestions for the restoration of these altered signaling pathways to potentially restore the drug sensitivity of tumor cells. Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1–mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy.
- Subjects
DRUG resistance in cancer cells; APOPTOSIS; ANTINEOPLASTIC agents; CELLULAR signal transduction; CELLULAR immunity; CELL lines; DNA damage; DRUG efficacy; GENOTYPES
- Publication
Cancers, 2024, Vol 16, Issue 5, p984
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16050984