Department of Gastroenterological Surgery, Osaka University, Suita, Osaka, Japan.
Department of Gastroenterological Surgery, Osaka Prefectural Hospital Organization, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan.
Ann Surg Oncol. 2021 Aug;28(8):4720-4732. doi: 10.1245/s10434-020-09373-x. Epub 2021 Jan 3.
Anticancer drugs generate excessive reactive oxygen species (ROS), which can cause cell death. Cancer cells can resist this oxidative stress, but the mechanism of resistance and associations with chemoresistance are unclear. Here, we focused on Sirtuin 3 (SIRT3), a deacetylating mitochondrial enzyme, in oxidative stress resistance in colorectal cancer (CRC).
To evaluate SIRT3-related changes in mitochondrial function, ROS (mtROS) induction, and apoptosis, we used the human CRC cell lines HT29 and HCT116 transfected with short-hairpin RNA targeting SIRT3 and small interfering RNAs targeting superoxide dismutase 2 mitochondrial (SOD2) and peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α). In 142 clinical specimens from patients with CRC, we also assessed the association of SIRT3 protein levels (high/low) and prognosis.
SIRT3 expression correlated with mtROS generation and apoptosis induction in cells treated with anticancer agents. Suppressing SIRT3 increased mtROS levels and cell sensitivity to anticancer agents. SIRT3 knockdown decreased SOD2 expression and activity, and suppressing SOD2 also improved sensitivity to anticancer drugs. In addition, SIRT3 was recruited with PGC-1α under oxidative stress, and suppressing SIRT3 decreased PGC-1α expression and mitochondrial function. PGC-1α knockdown decreased mitochondrial activity and increased apoptosis in cells treated with anticancer drugs. In resected CRC specimens, high vs low SIRT3 protein levels were associated with significantly reduced cancer-specific survival.
SIRT3 expression affected CRC cell chemoresistance through SOD2 and PGC-1α regulation and was an independent prognostic factor in CRC. SIRT3 may be a novel target for CRC therapies and a predictive marker of sensitivity to chemotherapy.
抗癌药物会产生过多的活性氧（ROS），从而导致细胞死亡。癌细胞可以抵抗这种氧化应激，但抵抗机制及其与化疗耐药性的关联尚不清楚。在这里，我们专注于 Sirtuin 3（SIRT3），一种去乙酰化的线粒体酶，研究其在结直肠癌（CRC）中的氧化应激抵抗作用。
为了评估 SIRT3 相关的线粒体功能、ROS（mtROS）诱导和细胞凋亡变化，我们使用靶向 SIRT3 的短发夹 RNA 和靶向超氧化物歧化酶 2 线粒体（SOD2）和过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）的小干扰 RNA 转染人 CRC 细胞系 HT29 和 HCT116。在 142 例 CRC 患者的临床标本中，我们还评估了 SIRT3 蛋白水平（高/低）与预后的关系。
SIRT3 表达与抗癌药物处理细胞中的 mtROS 产生和细胞凋亡诱导相关。抑制 SIRT3 增加了 mtROS 水平和细胞对抗癌药物的敏感性。SIRT3 敲低降低了 SOD2 的表达和活性，抑制 SOD2 也提高了抗癌药物的敏感性。此外，SIRT3 在氧化应激下与 PGC-1α 募集，抑制 SIRT3 降低了 PGC-1α 的表达和线粒体功能。PGC-1α 敲低降低了线粒体活性并增加了抗癌药物处理细胞的凋亡。在切除的 CRC 标本中，SIRT3 蛋白水平高与低与癌症特异性生存显著降低相关。
SIRT3 表达通过 SOD2 和 PGC-1α 调节影响 CRC 细胞的化疗耐药性，并且是 CRC 的独立预后因素。SIRT3 可能成为 CRC 治疗的新靶点和化疗敏感性的预测标志物。
