Lysosomal-Mitochondrial Interaction Promotes Tumor Growth in Squamous Cell Carcinoma of the Head and Neck.

IF 4.1 2区 医学 Q2 CELL BIOLOGY
Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri
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Abstract

Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other [lysosomal-mitochondrial interaction (LMI)] is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas [including squamous cell carcinoma of the head and neck (SCCHN)] overexpress transmembrane member 16A (TMEM16A), a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis; however, its impact on mitochondrial function has not been explored. In this study, we show that in the context of high-TMEM16A SCCHN, (i) patients display increased mitochondrial content, specifically complex I; (ii) in vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (iii) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (iv) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitate a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of LMI may serve as a therapeutic approach for patients with high TMEM16A-expressing SCCHN.

溶酶体/线粒体相互作用促进头颈部鳞状细胞癌的肿瘤生长。
包括溶酶体和线粒体在内的胞内细胞器之间的通信最近被证明可以调节细胞增殖和适应性。溶酶体和线粒体相互沟通的方式(溶酶体/线粒体相互作用,LMI)正在成为肿瘤增殖和生长的主要决定因素。约30%的鳞状癌(包括头颈部鳞状细胞癌,SCCHN)过表达TMEM16A,这是一种钙活化的氯离子通道,促进细胞生长并与患者生存负相关。我们最近表明TMEM16A驱动溶酶体的生物发生,但其对线粒体功能的影响尚未探讨。在这里,我们表明,在高TMEM16A SCCHN的背景下,(1)患者显示线粒体含量增加,特别是复合物I;(2)体外和体内模型的生长和存活完全依赖线粒体复合体I的活性;(3) NRF2信号是驱动线粒体功能的关键关键;(4)线粒体复合体I和溶酶体功能在增殖过程中相互依赖。综上所述,我们的数据表明,通过LMI协调的溶酶体和线粒体活性和生物发生驱动肿瘤增殖,并促进溶酶体和线粒体网络之间的功能相互作用。因此,抑制LMI恢复可能是SCCHN患者的一种治疗策略。意义:干预溶酶体-线粒体相互作用可能是治疗高TMEM16A表达SCCHN患者的一种方法。
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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
期刊介绍: Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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