BCL2A1 regulates Canady Helios Cold Plasma-induced cell death in triple-negative breast cancer

Abstract

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+ PR+/−HER2−), luminal B (ER+PR+/−HER2+), (ER−PR−HER2+), basal-like: ER−PR−HER2− 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.

Transcriptomic profiles‐based approach to decode the role of miR‐122 in triple negative breast cancer

“…Target genes were enriched in carcinogenic processes as cell cycle, cell communication, cellular response to stress and chemical stimulus, cellular senescence, HIF‐1 signaling pathway, and apoptosis. Moreover, targets genes as RUNX2 , HOXC13 , EGLN3 , BCL2A1 , CDC25A , KIF11 , and SOX11 among others have been reported as classical oncogenes in TNBC 45–52 . Highlight that most of them are transcription factors and regulators of differentiation and pluripotency.…”

“…Moreover, targets genes as RUNX2, HOXC13, EGLN3, BCL2A1, CDC25A, KIF11, and SOX11 among others have been reported as classical oncogenes in TNBC. [45][46][47][48][49][50][51][52] Highlight that most of them are transcription factors and regulators of differentiation and pluripotency.…”

Canady Cold Helios Plasma Reduces Soft Tissue Sarcoma Viability by Inhibiting Proliferation, Disrupting Cell Cycle, and Inducing Apoptosis: A Preliminary Report

“…Determining these would require a stand-alone study of its own. Moreover, in vitro follow-up studies will consider differential gene regulation as a mechanism of survival since we recently discovered BCL2A1 to be a key gene for CHCP resistance in breast cancers [44]. We anticipate that screening a panel of genes, associated with apoptosis (e.g., BCL2A1, TNF-α) and oxidative stress (e.g., APOE), will reveal therapeutic targets to increase STS susceptibility to CHCP for optimization of STS management.…”

Recent advances in cold atmospheric plasma (CAP) for breast cancer therapy

“…To date, the exact mechanism underlining the CAP selective effect on limited gene sets has remained elusive but supposed that the CAP inhibits the proliferation of cancer cells by regulating the methylation possess of H3K4 corresponding to oncogenes (Lee et al, 2018). The differentially regulation of genes upon CAP treatment can also originate from the degradation of histone mRNA during the cell cycle (Cheng et al, 2021; Murthy et al, 2022). Despite ambiguity around the precise cause of this phenomenon, preparing such expression profiles not only can develop our understanding of the underlying CAP mechanism of action but also can be used as a reliable marker to predict response to CAP therapy.…”