Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2).
Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2).
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DOI：
10.3390/cells12010179
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发表时间：
2023-01-01
期刊：
影响因子：
6
通讯作者：
Huang, Chun-Yin
中科院分区：
文献类型：
--
作者：
Chan, Chien-Yi;Hong, Shih-Cing;Chang, Chin-Ming;Chen, Yuan-Hong;Liao, Pin-Chen;Huang, Chun-Yin
口腔鳞状细胞癌（OSCC）通常具有高表皮生长因子受体（EGFR）表达。厄洛替尼是一种小分子酪氨酸激酶抑制剂（TKI），是EGFR活性的有效抑制剂；然而，可能会出现对该药物的耐药性，从而限制治疗结果。因此，在当前的研究中，我们的目标是揭示关键的细胞内分子和辅助试剂来克服厄洛替尼耐药性。首先，建立了两种HSC-3衍生的厄洛替尼耐药细胞系ERL-R5和ERL-R10；与亲本细胞相比，两者均表现出相对较高的生长速率、葡萄糖利用率、上皮间质转化（EMT）和侵袭性。 ERL-R 细胞中与癌症侵袭性相关的蛋白，如 N-钙粘蛋白、波形蛋白、Twist、MMP-2、MMP-9 和 MMP-13，以及糖酵解酶 PKM2 和 GLUT1 上调。值得注意的是，ERL-R 细胞对槲皮素敏感，槲皮素是一种天然存在的黄酮醇植物化学物质，对多种癌细胞具有抗癌特性。浓度为 5 μM 时，槲皮素可有效抑制细胞生长、降低葡萄糖利用率并抑制细胞侵袭。 ERL-R5 衍生的异种移植小鼠模型证实了槲皮素的生长抑制功效。此外，通过 siRNA 敲低 PKM2 模拟了槲皮素的作用，并使 ERL-R 细胞对厄洛替尼重新敏感。此外，添加槲皮素可通过增强细胞凋亡来阻止厄洛替尼介导的耐药性的发展。总之，我们的数据支持槲皮素在抗厄洛替尼耐药的 OSCC 中的应用，并表明 PKM2 是厄洛替尼耐药和槲皮素敏感性的决定因素。
Oral squamous cell carcinoma (OSCC) frequently carries high epidermal growth factor receptor (EGFR) expression. Erlotinib, a small molecule tyrosine kinase inhibitor (TKI), is an effective inhibitor of EGFR activity; however, resistance to this drug can occur, limiting therapeutic outcomes. Therefore, in the current study, we aimed to unveil key intracellular molecules and adjuvant reagents to overcome erlotinib resistance. First, two HSC-3-derived erlotinib-resistant cell lines, ERL-R5 and ERL-R10, were established; both exhibited relatively higher growth rates, glucose utilization, epithelial-mesenchymal transition (EMT), and invasiveness compared with parental cells. Cancer aggressiveness-related proteins, such as N-cadherin, Vimentin, Twist, MMP-2, MMP-9, and MMP-13, and the glycolytic enzymes PKM2 and GLUT1 were upregulated in ERL-R cells. Notably, ERL-R cells were sensitive to quercetin, a naturally-existing flavonol phytochemical with anti-cancer properties against various cancer cells. At a concentration of 5 μM, quercetin effectively arrested cell growth, reduced glucose utilization, and inhibited cellular invasiveness. An ERL-R5-derived xenograft mouse model confirmed the growth-inhibitory efficacy of quercetin. Additionally, knock-down of PKM2 by siRNA mimicked the effect of quercetin and re-sensitized ERL-R cells to erlotinib. Furthermore, adding quercetin blocked the development of erlotinib-mediated resistance by enhancing apoptosis. In conclusion, our data support the application of quercetin in anti-erlotinib-resistant OSCC and indicate that PKM2 is a determinant factor in erlotinib resistance and quercetin sensitivity.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.7603/s40681-016-0015-3
发表时间：
2016-06
期刊：
BioMedicine
影响因子：
--
作者：
Chan CY;Lien CH;Lee MF;Huang CY
通讯作者：
Huang CY
DOI：
10.1002/hed.26346
发表时间：
2020-07-17
影响因子：
2.9
作者：
Chan, Chien-Yi;Chang, Chin-Ming;Huang, Chun-Yin
通讯作者：
Huang, Chun-Yin
影响因子：
5.8
作者：
Ganthala, Parimala Devi;Alavala, Sateesh;Sistla, Ramakrishna
通讯作者：
Sistla, Ramakrishna
影响因子：
6.1
作者：
Jia, Lijun;Huang, Shan;Han, Lili
通讯作者：
Han, Lili