RESUMO
Inhibition of the RAF-MEK1/2-ERK signaling pathway is an ideal strategy for treating cancers with NRAS or BRAF mutations. However, the development of resistance due to incomplete inhibition of the pathway and activation of compensatory cell proliferation pathways is a major impediment of the targeted therapy. The anthrax lethal toxin (LT), which cleaves and inactivates MEKs, is a modifiable biomolecule that can be delivered selectively to tumor cells and potently kills various tumor cells. However, resistance to LT and the mechanism involved are yet to be explored. Here, we show that LT, through inhibiting MEK1/2-ERK activation, inhibits the proliferation of cancer cells with NRAS/BRAF mutations. Among them, the human colorectal tumor HT-29 and murine melanoma B16-BL6 cells developed resistance to LT in 2 to 3 days of treatment. These resistant cells activated AKT through a histone deacetylase (HDAC) 8-dependent pathway. Using an Affymetrix microarray, followed by qPCR validation, we identified that the differential expression of the phospholipase C-ß1 (PLCB1) and squamous cell carcinoma-1 (DESC1) played an important role in HDAC8-mediated AKT activation and resistance to MEK1/2-ERK inhibition. By using inhibitors, small interference RNAs and/or expression vectors, we found that the inhibition of HDAC8 suppressed PLCB1 expression and induced DESC1 expression in the resistant cells, which led to the inhibition of AKT and re-sensitization to LT and MEK1/2 inhibition. These results suggest that targeting PLCB1 and DESC1 is a novel strategy for inhibiting the resistance to MEK1/2 inhibition.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Histona Desacetilases/metabolismo , Proteínas de Membrana/metabolismo , Fosfolipase C beta/metabolismo , Proteínas Repressoras/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antígenos de Bactérias/toxicidade , Toxinas Bacterianas/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HT29 , Humanos , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Proteínas de Membrana/genética , Camundongos , Fosfolipase C beta/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Serina Endopeptidases/genéticaRESUMO
The World Health Organization (WHO) recently endorsed the proposal for a Decade of Healthy Ageing (2020-2030). The WHO defines "healthy aging" as "the process of developing and maintaining the functional ability that enables wellbeing in older age." Among the strategies for the Decade of Healthy Ageing, the WHO has suggested enhancing intrinsic capacity, promoting functional ability, and implementing the Integrated Care for Older People (ICOPE) package. The WHO has defined steps for ICOPE evaluation and scale-up and is performing a prospective study in 2-3 countries (low and middle income, high income) to test its feasibility in 2021-2022 and a multinational randomized study to validate its clinical efficacy and effectiveness in 2022-2024. Intrinsic capacity and frailty represent two faces of the same coin, with one indicating the reserves of the individual and the other indicating the deficits that accumulate with age. The Integrated Care of Older Patients with Frailty in Primary Care (ICOOP_Frail) study is the first integrated care program for frailty or functional decline in primary care in Korea. The results suggest that the ICOOP_Frail study can be utilized as a reference for ICOPE studies in Korea or at least to provide important findings for the forthcoming ICOPE implementation study in Korea.