MTHFD2 Blockade Enhances the Efficacy of β-Lapachone Chemotherapy With Ionizing Radiation in Head and Neck Squamous Cell Cancer.
MTHFD2 Blockade Enhances the Efficacy of β-Lapachone Chemotherapy With Ionizing Radiation in Head and Neck Squamous Cell Cancer.
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DOI：
10.3389/fonc.2020.536377
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发表时间：
2020
影响因子：
4.7
通讯作者：
Furdui CM
中科院分区：
文献类型：
--
作者：
Shukla K;Singh N;Lewis JE;Tsang AW;Boothman DA;Kemp ML;Furdui CM
头颈部鳞状细胞癌（HNSCC）提出了多种治疗挑战，限制了总体生存率并影响了患者的生活质量。其中，对放射治疗的耐药性是HNSCC患者的主要临床问题，这与肿瘤的起源、位置和肿瘤分级有关，限制了肿瘤的控制。虽然顺铂被认为是最终或辅助放疗的标准放射增敏剂，但在复发性肿瘤或姑息治疗中，其他化疗药物，如抗叶酸类药物甲氨蝶呤或培美曲塞也被用作放射增敏剂。这些药物抑制二氢叶酸还原酶，二氢叶酸还原酶对DNA合成至关重要，并将1-C/叶酸代谢与细胞内NAD(P)H和NAD(P)+平衡联系起来。在之前的研究中，我们发现MTHFD2是一种参与叶酸代谢的线粒体酶，是耐辐射细胞和HNSCC肿瘤中NAD(P)H水平的关键因素。在本研究中，我们研究了MTHFD2在单独和与β-lapachone（一种NQO1生物活化药物）联合辐射反应中的作用，β-lapachone可产生伴随NAD(P)H氧化为NAD(P)+的活性氧。这些研究是在匹配的HNSCC细胞对辐射的反应模型中进行的：耐辐射的rSCC-61和辐射敏感的SCC-61细胞。与SCC-61相比，耐辐射rSCC-61细胞对β-lapachone的敏感性增加，rSCC-61细胞中MTHFD2的下调进一步增强了β-lapachone的辐射毒性，并呈剂量和时间依赖性。rSCC-61 MTHFD2敲低细胞经β-lapachone辐照和处理后，与对照rSCC-61打乱shRNA相比，PARP1激活增加，线粒体呼吸抑制，呼吸相关ATP产生减少，线粒体超氧化物和蛋白质氧化增加。因此，这些研究表明MTHFD2是开发放射增敏化疗药物和β-lapachone细胞毒性增强剂的潜在靶点。
Head and Neck Squamous Cell Cancer (HNSCC) presents with multiple treatment challenges limiting overall survival rates and affecting patients' quality of life. Amongst these, resistance to radiation therapy constitutes a major clinical problem in HNSCC patients compounded by origin, location, and tumor grade that limit tumor control. While cisplatin is considered the standard radiosensitizing agent for definitive or adjuvant radiotherapy, in recurrent tumors or for palliative care other chemotherapeutics such as the antifolates methotrexate or pemetrexed are also being utilized as radiosensitizers. These drugs inhibit the enzyme dihydrofolate reductase, which is essential for DNA synthesis and connects the 1-C/folate metabolism to NAD(P)H and NAD(P)+ balance in cells. In previous studies, we identified MTHFD2, a mitochondrial enzyme involved in folate metabolism, as a key contributor to NAD(P)H levels in the radiation-resistant cells and HNSCC tumors. In the study presented here, we investigated the role of MTHFD2 in the response to radiation alone and in combination with β-lapachone, a NQO1 bioactivatable drug, which generates reactive oxygen species concomitant with NAD(P)H oxidation to NAD(P)+. These studies are performed in a matched HNSCC cell model of response to radiation: the radiation resistant rSCC-61 and radiation sensitive SCC-61 cells reported earlier by our group. Radiation resistant rSCC-61 cells had increased sensitivity to β-lapachone compared to SCC-61 and knockdown of MTHFD2 in rSCC-61 cells further potentiated the cytotoxicity of β-lapachone with radiation in a dose and time-dependent manner. rSCC-61 MTHFD2 knockdown cells irradiated and treated with β-lapachone showed increased PARP1 activation, inhibition of mitochondrial respiration, decreased respiration-linked ATP production, and increased mitochondrial superoxide and protein oxidation as compared to control rSCC-61 scrambled shRNA. Thus, these studies point to MTHFD2 as a potential target for development of radiosensitizing chemotherapeutics and potentiator of β-lapachone cytotoxicity.
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影响因子：
4.6
作者：
Holmila RJ;Vance SA;Chen X;Wu H;Shukla K;Bharadwaj MS;Mims J;Wary Z;Marrs G;Singh R;Molina AJ;Poole LB;King SB;Furdui CM
通讯作者：
Furdui CM
过氧化氢酶消除了NQO1阳性乳腺癌中的β-拉帕酮诱导的PARP1过度激活导向的坏死。
影响因子：
5.7
作者：
Bey EA;Reinicke KE;Srougi MC;Varnes M;Anderson VE;Pink JJ;Li LS;Patel M;Cao L;Moore Z;Rommel A;Boatman M;Lewis C;Euhus DM;Bornmann WG;Buchsbaum DJ;Spitz DR;Gao J;Boothman DA
通讯作者：
Boothman DA
影响因子：
50.3
作者：
Huang X;Motea EA;Moore ZR;Yao J;Dong Y;Chakrabarti G;Kilgore JA;Silvers MA;Patidar PL;Cholka A;Fattah F;Cha Y;Anderson GG;Kusko R;Peyton M;Yan J;Xie XJ;Sarode V;Williams NS;Minna JD;Beg M;Gerber DE;Bey EA;Boothman DA
通讯作者：
Boothman DA
影响因子：
7.4
作者：
Dias, Rosane Borges;Sacramento de Araujo, Tais Bacelar;Gurgel Rocha, Clarissa Araujo
通讯作者：
Gurgel Rocha, Clarissa Araujo
影响因子：
6.6
作者：
Bansal, Nidhi;Mims, Jade;Furdui, Cristina M.
通讯作者：
Furdui, Cristina M.