Cancer Research @UCC, College of Medicine and Health, University College Cork, Cork, Ireland.
Cancer Med. 2024 Sep;13(17):e70173. doi: 10.1002/cam4.70173.
Esophageal cancer is a poor prognosis cancer characterized by intrinsic or acquired resistance to chemotherapeutic agents. The primary determinants of treatment failure are unknown. Expression of an anti-viral protein, myxovirus resistance protein A (MxA) is de-regulated in many cancers, including esophageal cancer, and its activity has been linked to apoptosis. This study has assessed whether MxA expression can influence the response of esophageal cancer cells to the chemotherapeutic agents 5-fluorouracil (5-FU) or oxaliplatin. MxA protein was differentially expressed in a panel of five esophageal cancer cell lines. KYSE450 and KYSE140 cells did not express MxA and were apoptosis incompetent. FLO-1, KYSE270, and OE21 cells expressed MxA, were more drug-sensitive and were apoptosis competent. MxA was artificially overexpressed in cell lines with no endogenous expression (KYSE450 and KYSE140). This increased the resistance of KYSE450 but not KYSE140 cells. Both cell lines remained apoptosis incompetent. We then evaluated siRNA knockdown of MxA in FLO-1 cells and CRISPR knockout in OE21 cells. Knockdown of MxA significantly increased drug sensitivity and caspase-3 activation in FLO-1 cells. OE21-MX1 cells were also more drug-sensitive, but in contrast to FLO-1 cells, caspase-3 activation was reduced. Collectively these data indicate that MxA can promote resistance to chemotherapy, but this does not always correspond with effects on apoptosis. Effects on apoptosis are cell line specific, suggesting that other co-operating pathways determine the overall impact of MxA. Importantly, in cancer cells that overexpress the protein, drug sensitivity can be improved by interfering with MxA.
食管癌是一种预后不良的癌症，其特征是对化疗药物存在内在或获得性耐药。治疗失败的主要决定因素尚不清楚。抗病毒蛋白肌氨酸脱氨酶蛋白 A（MxA）在许多癌症中表达失调，包括食管癌，其活性与细胞凋亡有关。本研究评估了 MxA 表达是否能影响食管癌细胞对化疗药物 5-氟尿嘧啶（5-FU）或奥沙利铂的反应。MxA 蛋白在五株食管癌细胞系的表达存在差异。KYSE450 和 KYSE140 细胞不表达 MxA，且无细胞凋亡能力。FLO-1、KYSE270 和 OE21 细胞表达 MxA，对药物更敏感，且有细胞凋亡能力。在无内源性表达的细胞系（KYSE450 和 KYSE140）中人工过表达 MxA。这增加了 KYSE450 细胞的耐药性，但不增加 KYSE140 细胞的耐药性。这两种细胞系仍无细胞凋亡能力。然后，我们评估了 FLO-1 细胞中 MxA 的 siRNA 敲低和 OE21 细胞中的 CRISPR 敲除。FLO-1 细胞中 MxA 的敲低显著增加了药物敏感性和半胱天冬酶-3 的激活。OE21-MX1 细胞也对药物更敏感，但与 FLO-1 细胞相反，半胱天冬酶-3 的激活减少。这些数据表明，MxA 可以促进对化疗的耐药性，但这并不总是与细胞凋亡的影响相对应。细胞凋亡的影响具有细胞系特异性，这表明其他合作途径决定了 MxA 的总体影响。重要的是，在过度表达该蛋白的癌细胞中，通过干扰 MxA 可以提高药物敏感性。
