RSK2调控肿瘤细胞自噬的分子机制及其对乳腺癌治疗的影响

Targeting autophagy is now considered a novel strategy for cancer therapy; thus, a better understanding of the molecular mechanisms and signaling pathways underlying the regulation of autophagy may help identify novel therapeutic targets for anti-cancer drug development. p90 ribosomal S6 kinase 2 (RSK2), a serine/threonine protein kinase that is overexpressed in breast cancer cells and tissues, was reported to be implicated in control of breast cancer cell growth and proliferation; yet, the related molecular mechanisms remain unclear. Recently, we found that RSK2 plays a critical role in regulating the ER stress and metabolic stress-induced autophagy, providing the first evidence for the regulatory role of RSK2 in autophagy. To explore the pathway linking RSK2 activation and ER stress, we determined the role of IRE1α, an ER membrane-associated protein that mediates UPR and alleviates ER stress, and found that IRE1α was required for activation of RSK2 under ER stress. AMP-activated protein kinase (AMPK), an energy sensor regulating cellular metabolism and a positive regulator of autophagy, appeared to participate in the RSK2-activated autophagy, as silencing of RSK2 expression caused a reduction in the level of phospho-AMPK. In this grant application, we propose to investigate the molecular mechanisms of autophagy regulated by RSK2 in breast cancer cells under various stresses, and to elucidate the IRE1α-RSK2-AMPK as a novel signaling pathway in the regulation of autophagy in cancer cells. We will explore whether targeting the RSK2-mediated autophagy can inhibit tumor initiation, progression and invasion, and enhance the sensitivity of tumor cells to anti-cancer treatment. The proposed study may not only provide a better understanding of the biology and pathophysiology of autophagy, but also present a new rationale for developing more effective and better therapies for breast cancer, and a new pharmacologic target for drug development.

靶向自噬作为一种新的肿瘤治疗策略日渐引起广泛关注，深入探索自噬发生的分子机制将有利于肿瘤治疗新靶点的发现和新药研发。p90核糖体 S6蛋白激酶2（RSK2）在乳腺癌中高表达，可能是促进癌细胞增殖的关键调节因子，但相关机制尚未明确。申请人最新研究发现，RSK2介导乳腺癌细胞各种压力条件下自噬的发生，首次揭示了RSK2在自噬调控中的关键作用。RSK2活化受到内质网应激信号通路激活因IRE1α的调控，应激条件下RSK2影响自噬调节蛋白AMPK的激活。本项目拟进一步阐明RSK2调控乳腺癌细胞自噬的分子机制，揭示一条新的信号传导通路，即IRE1α-RSK2-AMPK在肿瘤细胞自噬调控中的作用；探索抑制RSK2介导的自噬对乳腺癌发生、发展和转移的影响；确定靶向RSK2以抑制自噬能否增强乳腺癌的治疗效果。本研究旨在进一步揭示新的自噬调控通路和调节因子，为开发新药、提高乳腺癌的治疗效果提供科学依据。

乳腺癌是女性最常见的恶性肿瘤之一，随着早期诊断方法、治疗手段和预后检测手段的不断普及和完善，我国乳腺癌患者的生存率显著升高，但是其发病率和死亡率仍然位于女性全身恶性肿瘤的首位。目前，导致乳腺癌治疗失败的主要原因是乳腺癌细胞对药物治疗产生耐受性和远处转移。细胞自噬是真核生物细胞内普遍存在的一种维持自我稳态的机制，在促进乳腺癌细胞增殖和转移中发挥重要作用。同时，细胞自噬可以帮助肿瘤细胞适应各种应激条件，降低肿瘤细胞对放、化疗的敏感性。因此，靶向自噬作为一种新的肿瘤治疗策略日渐引起广泛关注。p90核糖体S6蛋白激酶2（RSK2）在乳腺癌中高表达，是应激条件下促进乳腺癌细胞存活的关键因子，但相关机制尚未明确。我们研究发现，乳腺癌细胞中内质网应激条件下RSK2能够被激活，并介导细胞自噬的发生，首次揭示了RSK2在自噬调控中的关键作用。进一步揭示内质网应激激活RSK2的机制发现，内质网应激信号通路关键蛋白IRE1α通过ERK1/2激活RSK2。RSK2与AMPK相互结合磷酸化导致其激活，从而诱导细胞自噬。体内外实验表明，干扰RSK2可抑制乳腺癌细胞增殖，促进内质网应激诱导的细胞凋亡。同时，我们的研究也表明靶向RSK2抑制自噬能够增强紫杉醇对乳腺癌细胞的治疗效果。该研究为乳腺癌的靶向治疗、新药研发以及提高乳腺癌的临床治疗效果提供了新的实验依据。

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