Jerome Canady Research Institute for Advanced Biological and Technological Sciences, Takoma Park, MD, USA.
Plasma Medicine Life Sciences, Takoma Park, MD, USA.
Sci Rep. 2022 Mar 8;12(1):4038. doi: 10.1038/s41598-022-07027-4.
Breast cancer is the leading cause of cancer death among women. Triple-negative breast cancer (TNBC) has a poor prognosis and frequently relapses early compared with other subtypes. The Cold Atmospheric Plasma (CAP) is a promising therapy for prognostically poor breast cancer such as TNBC. The Canady Helios Cold Plasma (CHCP) induces cell death in the TNBC cell line without thermal damage, however, the mechanism of cell death by CAP treatment is ambiguous and the mechanism of resistance to cell death in some subset of cells has not been addressed. We investigate the expression profile of 48 apoptotic and 35 oxidative gene markers after CHCP treatment in six different types of breast cancer cell lines including luminal A (ER PRHER2), luminal B (ERPRHER2), (ERPRHER2), basal-like: ERPRHER2 cells were tested with CHCP at different power settings and at 4 different incubation time. The expression levels of the gene markers were determined at 4 different intervals after the treatment. The protein expression of BCL2A1 was only induced after CHCP treatment in TNBC cell lines (p < 0.01), whereas the HER2-positive and ER, PR positive cell lines showed little or no expression of BCL2A1. The BCL2A1 and TNF-alpha expression levels showed a significant correlation within TNBC cell lines (p < 0.01). Silencing BCL2A1 mRNA by siRNA increased the potency of the CHCP treatment. A Combination of CHCP and CPI203, a BET bromodomain inhibitor, and a BCL2A1 antagonist increased the CHCP-induced cell death (p < 0.05). Our results revealed that BCL2A1 is a key gene for resistance during CHCP induced cell death. This resistance in TNBCs could be reversed with a combination of siRNA or BCL2A1 antagonist-CHCP therapy.
乳腺癌是女性癌症死亡的主要原因。与其他亚型相比，三阴性乳腺癌（TNBC）预后较差，且常早期复发。冷大气压等离子体（CAP）是一种有前途的治疗方法，可用于预后不良的乳腺癌，如 TNBC。Canady Helios 冷等离子体（CHCP）在不产生热损伤的情况下诱导 TNBC 细胞系中的细胞死亡，然而，CAP 治疗诱导细胞死亡的机制尚不清楚，并且某些亚群细胞对细胞死亡的抵抗机制尚未得到解决。我们研究了 CHCP 处理后六种不同类型乳腺癌细胞系（包括 luminal A [ER PRHER2]、luminal B [ERPRHER2]、HER2 阳性、基底样：ERPRHER2 细胞）中 48 个凋亡和 35 个氧化基因标志物的表达谱，在不同功率设置和 4 个不同孵育时间下用 CHCP 测试细胞。在处理后 4 个不同时间间隔测定基因标志物的表达水平。只有在 TNBC 细胞系中，BCL2A1 的蛋白表达在 CHCP 处理后才被诱导（p < 0.01），而 HER2 阳性和 ER、PR 阳性细胞系中 BCL2A1 的表达很少或没有。BCL2A1 和 TNF-α 表达水平在 TNBC 细胞系中呈显著相关性（p < 0.01）。用 siRNA 沉默 BCL2A1 mRNA 增加了 CHCP 处理的效力。CHCP 与 BET 溴结构域抑制剂 CPI203 和 BCL2A1 拮抗剂的组合增加了 CHCP 诱导的细胞死亡（p < 0.05）。我们的结果表明，BCL2A1 是 CHCP 诱导细胞死亡过程中耐药的关键基因。TNBC 中的这种耐药性可以通过 siRNA 或 BCL2A1 拮抗剂-CHCP 治疗的组合来逆转。
