Gene regulatory networking reveals the molecular cue to lysophosphatidic acid-induced metabolic adaptations in ovarian cancer cells.
Gene regulatory networking reveals the molecular cue to lysophosphatidic acid-induced metabolic adaptations in ovarian cancer cells.
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DOI：
10.1002/1878-0261.12046
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发表时间：
2017-05
影响因子：
6.6
通讯作者：
Roy SS
中科院分区：
文献类型：
--
作者：
Ray U;Roy Chowdhury S;Vasudevan M;Bankar K;Roychoudhury S;Roy SS
外渗和转移性进展是与癌症相关的高死亡率的两个主要原因。癌细胞的转移潜力取决于肿瘤微环境中普遍存在的大量代谢挑战。为了实现更高的增殖率，癌细胞重新编程其代谢，增加糖酵解和生物合成活性。为什么这种代谢重编程使细胞倾向于增加肿瘤发生仍然是一个谜。肿瘤微环境中无数的瘤脂的积累已被证明会促进癌细胞的侵袭性，溶血磷脂酸（LPA）是卵巢癌患者中富集的一种关键因子。细胞生物能量研究证实，与非转化上皮细胞相比，卵巢癌细胞长期暴露于LPA后，氧化磷酸化受到抑制，糖酵解增加。我们试图揭示这种肿瘤脂质诱导的代谢扰动背后的调控复杂性。使用RNA-Seq分析的基因调控网络将癌基因ETS-1确定为LPA诱导的代谢改变的关键介质，以维持侵袭性表型。此外，LPA受体-2特异性PtdIns 3 K-AKT信号传导诱导ETS-1及其靶向基质金属蛋白酶。ETS-1的去除恢复细胞生物能量学，增加氧化磷酸化和减少糖酵解，这种作用被LPA的存在逆转。此外，LPA处理的卵巢癌细胞的生物能量状态通过诱导缺氧诱导因子-1 α模拟缺氧，发现缺氧诱导因子-1 α反式激活ets-1。在同系小鼠中产生的原发性肿瘤的研究证实了体外发现。因此，我们的研究强调了卵巢癌细胞中促转移因子ETS-1诱导的表型变化。增强的侵袭性和代谢可塑性之间的关系进一步说明了癌细胞的代谢适应作为肿瘤进展的驱动因素的关键作用。这些发现揭示了肿瘤脂质诱导的代谢易感性是肿瘤发生的一种新机制，并提出代谢抑制剂作为未来管理侵袭性卵巢癌的潜在方法。
Extravasation and metastatic progression are two main reasons for the high mortality rate associated with cancer. The metastatic potential of cancer cells depends on a plethora of metabolic challenges prevailing within the tumor microenvironment. To achieve higher rates of proliferation, cancer cells reprogram their metabolism, increasing glycolysis and biosynthetic activities. Just why this metabolic reprogramming predisposes cells towards increased oncogenesis remains elusive. The accumulation of myriad oncolipids in the tumor microenvironment has been shown to promote the invasiveness of cancer cells, with lysophosphatidic acid (LPA) being one such critical factor enriched in ovarian cancer patients. Cellular bioenergetic studies confirm that oxidative phosphorylation is suppressed and glycolysis is increased with long exposure to LPA in ovarian cancer cells compared with non‐transformed epithelial cells. We sought to uncover the regulatory complexity underlying this oncolipid‐induced metabolic perturbation. Gene regulatory networking using RNA‐Seq analysis identified the oncogene ETS‐1 as a critical mediator of LPA‐induced metabolic alterations for the maintenance of invasive phenotype. Moreover, LPA receptor‐2 specific PtdIns3K‐AKT signaling induces ETS‐1 and its target matrix metalloproteases. Abrogation of ETS‐1 restores cellular bioenergetics towards increased oxidative phosphorylation and reduced glycolysis, and this effect was reversed by the presence of LPA. Furthermore, the bioenergetic status of LPA‐treated ovarian cancer cells mimics hypoxia through induction of hypoxia‐inducible factor‐1α, which was found to transactivate ets‐1. Studies in primary tumors generated in syngeneic mice corroborated the in vitro findings. Thus, our study highlights the phenotypic changes induced by the pro‐metastatic factor ETS‐1 in ovarian cancer cells. The relationship between enhanced invasiveness and metabolic plasticity further illustrates the critical role of metabolic adaptation of cancer cells as a driver of tumor progression. These findings reveal oncolipid‐induced metabolic predisposition as a new mechanism of tumorigenesis and propose metabolic inhibitors as a potential approach for future management of aggressive ovarian cancer.
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影响因子：
37.3
作者：
Basu M;Bhattacharya R;Ray U;Mukhopadhyay S;Chatterjee U;Roy SS
通讯作者：
Roy SS
影响因子：
--
作者：
Ha JH;Ward JD;Radhakrishnan R;Jayaraman M;Song YS;Dhanasekaran DN
通讯作者：
Dhanasekaran DN
影响因子：
--
作者：
Fan Q;Cai Q;Xu Y
通讯作者：
Xu Y
影响因子：
6.4
作者：
Langbein, Sigrun;Frederiks, Wilma M.;Coy, Johannes F.
通讯作者：
Coy, Johannes F.
影响因子：
4.8
作者：
Ghosh, Sonali;Basu, Moitri;Roy, Sib Sankar
通讯作者：
Roy, Sib Sankar