Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy.
Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy.
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DOI：
10.1073/pnas.2100670119
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发表时间：
2022-03-22
影响因子：
11.1
通讯作者：
Duvvuri U
中科院分区：
文献类型：
--
作者：
Vyas A;Gomez-Casal R;Cruz-Rangel S;Villanueva H;Sikora AG;Rajagopalan P;Basu D;Pacheco J;Hammond GRV;Kiselyov K;Duvvuri U
顺铂是头颈癌患者的一线治疗药物。然而，对顺铂的耐药性仍然是一个主要问题。肿瘤中钙激活氯离子通道 TMEM16A 的高表达预示着这些患者的生存率较差，这可能是由于耐药性所致。在这里，我们证明 TMEM16A 驱动顺铂隔离到溶酶体中。随后，顺铂通过溶酶体递送至细胞表面而被排出。我们发现 TMEM16A 增强了这一过程，从而促进顺铂耐药。我们还表明，溶酶体抑制与顺铂协同作用，诱导肿瘤细胞死亡。我们的数据揭示了溶酶体生理学和癌细胞生物学的一个新的基本特征，可能会影响头颈癌患者的治疗。头颈鳞状细胞癌（SCCHN）是一种毁灭性的疾病，尽管最近治疗方法取得了进展，但治愈率仍然很低。顺铂是最常用的化疗药物，治疗失败很大程度上是由于对该药物的耐药性造成的。约 30% 的 SCCHN 肿瘤中出现染色体带 11q13 扩增。该区域包含编码 TMEM16A 离子通道的 ANO1 基因，该离子通道负责上皮组织中钙激活的氯离子转运。 TMEM16A 过度表达与顺铂耐药相关，高 TMEM16A 水平与生存率降低相关。然而，这种效应的机制基础仍然未知。溶酶体生物发生和胞吐作用与癌症有关，因为它们在受损细胞器的清除以及化疗药物和毒素的胞吐作用中发挥作用。在这里，我们发现TMEM16A过表达促进溶酶体生物合成和胞吐作用，这与细胞内顺铂的排出一致。通过结合遗传和药理学方法，我们发现 TMEM16A 以需要活性氧、TRPML1 和激活 β-连环蛋白-黑素细胞诱导转录因子途径的方式促进溶酶体通量。溶酶体抑制剂羟氯喹 (HCQ) 与顺铂协同作用，在体外杀死 SCCHN 细胞。使用 SCCHN 小鼠模型，我们发现 HCQ 和顺铂可延缓顺铂耐药的患者来源的体内异种移植物的生长。我们认为 TMEM16A 通过上调溶酶体隔离和细胞毒性药物的胞吐作用来实现细胞存活。这些结果揭示了癌症耐药性的治疗模型、其逆转以及 TMEM16A 的作用。
Cisplatin is the first line therapy for patients with head and neck cancer. However, resistance to cisplatin remains a major concern. High expression of the calcium-activated chloride channel TMEM16A in tumors portends poor survival in these patients, possibly because of drug resistance. Here, we show that TMEM16A drives the sequestration of cisplatin into lysosomes. Subsequently, cisplatin is expelled via the delivery of lysosomes to the cell surface. We show that TMEM16A enhances this process, thereby promoting cisplatin resistance. We also show that lysosomal inhibition synergizes with cisplatin to induce tumor cell death. Our data uncovers a new fundamental feature of both lysosomal physiology and cancer cell biology that can potentially impact the treatment of patients with head and neck cancer. Squamous cell carcinoma of the head and neck (SCCHN) is a devastating disease that continues to have low cure rates despite the recent advances in therapies. Cisplatin is the most used chemotherapy agent, and treatment failure is largely driven by resistance to this drug. Amplification of chromosomal band 11q13 occurs in ∼30% of SCCHN tumors. This region harbors the ANO1 gene that encodes the TMEM16A ion channel, which is responsible for calcium-activated chloride transport in epithelial tissues. TMEM16A overexpression is associated with cisplatin resistance, and high TMEM16A levels correlate with decreased survival. However, the mechanistic underpinning of this effect remains unknown. Lysosomal biogenesis and exocytosis have been implicated in cancer because of their roles in the clearance of damaged organelles and exocytosis of chemotherapeutic drugs and toxins. Here, we show that TMEM16A overexpression promotes lysosomal biogenesis and exocytosis, which is consistent with the expulsion of intracellular cisplatin. Using a combination of genetic and pharmacologic approaches, we find that TMEM16A promotes lysosomal flux in a manner that requires reactive oxygen species, TRPML1, and the activation of the β-catenin–melanocyte-inducing transcription factor pathway. The lysosomal inhibitor hydroxychloroquine (HCQ) synergizes with cisplatin in killing SCCHN cells in vitro. Using a murine model of SCCHN, we show that HCQ and cisplatin retard the growth of cisplatin-resistant patient-derived xenografts in vivo. We propose that TMEM16A enables cell survival by the up-regulation of lysosomal sequestration and exocytosis of the cytotoxic drugs. These results uncover a model of treatment for resistance in cancer, its reversal, and a role for TMEM16A.
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影响因子：
5.2
作者：
López-Verdín S;Lavalle-Carrasco J;Carreón-Burciaga RG;Serafín-Higuera N;Molina-Frechero N;González-González R;Bologna-Molina R
通讯作者：
Bologna-Molina R
影响因子：
168.9
作者：
Mehanna, Hisham;Robinson, Max;Dunn, Janet
通讯作者：
Dunn, Janet
影响因子：
4.8
作者：
Bill, Anke;Popa, M. Oana;Gaither, L. Alex
通讯作者：
Gaither, L. Alex
影响因子：
6.4
作者：
Facompre ND;Rajagopalan P;Sahu V;Pearson AT;Montone KT;James CD;Gleber-Netto FO;Weinstein GS;Jalaly J;Lin A;Rustgi AK;Nakagawa H;Califano JA;Pickering CR;White EA;Windle BE;Morgan IM;Cohen RB;Gimotty PA;Basu D
通讯作者：
Basu D
DOI：
10.1158/1078-0432.ccr-17-1561
发表时间：
2017-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Godse NR;Khan N;Yochum ZA;Gomez-Casal R;Kemp C;Shiwarski DJ;Seethala RS;Kulich S;Seshadri M;Burns TF;Duvvuri U
通讯作者：
Duvvuri U