Second mitochondrial-derived activator of caspase (SMAC), also known as direct inhibitor of apoptosis-binding proteins with low pI (Diablo), is known as a pro-apoptotic mitochondrial protein released into the cytosol in response to apoptotic signals. We recently reported SMAC overexpression in cancers as essential for cell proliferation and tumor growth due to non-apoptotic functions, including phospholipid synthesis regulation. These functions may be associated with its interactions with partner proteins. Using a peptide array with 768 peptides derived from 11 selected SMAC-interacting proteins, we identified SMAC-interacting sequences. These SMAC-binding sequences were produced as cell-penetrating peptides targeted to the cytosol, mitochondria, or nucleus, inhibiting cell proliferation and inducing apoptosis in several cell lines. For study, a survivin/baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5)-derived peptide was selected, due to its overexpression in many cancers and its involvement in mitosis, apoptosis, autophagy, cell proliferation, inflammation, and immune responses, as a target for cancer therapy. Specifically, a SMAC-targeting survivin/BIRC5-derived peptide, given intratumorally or intravenously, strongly inhibited lung tumor growth, cell proliferation, angiogenesis, and inflammation, induced apoptosis, and remodeled the tumor microenvironment. The peptide promoted tumor infiltration of CD-8 cells and increased cell-intrinsic programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, resulting in cancer cell self-destruction and increased tumor cell death, preserving immune cells. Thus, targeting the interaction between the multifunctional proteins SMAC and survivin represents an innovative therapeutic cancer paradigm.

中文翻译：

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SMAC 与存活蛋白衍生肽的相互作用改变了基本的癌症标志：肿瘤生长、炎症和免疫抑制


第二种线粒体衍生的半胱天冬酶激活剂 (SMAC)，也称为低 pI 的凋亡结合蛋白的直接抑制剂 (Diablo)，是一种促凋亡线粒体蛋白，响应凋亡信号释放到细胞质中。我们最近报道，由于非凋亡功能（包括磷脂合成调节），SMAC 在癌症中过度表达对于细胞增殖和肿瘤生长至关重要。这些功能可能与其与伙伴蛋白的相互作用有关。使用包含源自 11 种选定的 SMAC 相互作用蛋白的 768 种肽的肽阵列，我们鉴定了 SMAC 相互作用序列。这些 SMAC 结合序列作为细胞穿透肽产生，靶向细胞质、线粒体或细胞核，抑制细胞增殖并诱导多种细胞系凋亡。为了进行研究，选择了含有生存素/杆状病毒凋亡重复序列 5 (BIRC5) 衍生肽的抑制剂，因为它在许多癌症中过度表达，并且参与有丝分裂、细胞凋亡、自噬、细胞增殖、炎症和免疫反应，如癌症治疗的目标。具体而言，肿瘤内或静脉注射的 SMAC 靶向存活蛋白/BIRC5 衍生肽可强烈抑制肺肿瘤生长、细胞增殖、血管生成和炎症，诱导细胞凋亡，并重塑肿瘤微环境。该肽促进CD-8细胞的肿瘤浸润并增加细胞内在程序性细胞死亡蛋白1（PD-1）和程序性细胞死亡配体1（PD-L1）的表达，导致癌细胞自我毁灭并增加肿瘤细胞死亡，保存免疫细胞。 因此，针对多功能蛋白 SMAC 和生存素之间的相互作用代表了一种创新的癌症治疗范例。