Cell Signaling and Cancer Biology Laboratory, Department of Biochemistry, Guindy Campus, University of Madras, Chennai 600025, India.
Cell Signaling and Cancer Biology Laboratory, Department of Biochemistry, Guindy Campus, University of Madras, Chennai 600025, India.
Biochim Biophys Acta Mol Cell Res. 2021 Apr;1868(5):118975. doi: 10.1016/j.bbamcr.2021.118975. Epub 2021 Feb 2.
The Salt-inducible kinase (SIKs) belongs to an AMPK-related family kinase, an isoform of the SIK family, SIK1 gets frequently downregulated in various types of cancer contribute to tumorigenesis. However, its precise role in breast cancer and the relevant molecular mechanism remains unclear. Herein, analysis of the clinical data reveals that SIK1 expression was significantly downregulated in breast cancer tissues, and closely associated with poor survival rate in breast cancer. SIK1 is functionally stimulating oxidative phosphorylation, which in turn inhibits aerobic glycolysis and cell proliferation in breast cancer cells. Mechanistically, SIK1 directly interacted with p53 and positively regulates its transcriptional activity, thereby facilitates oxidative phosphorylation in breast cancer cells. The knockdown of SIK1 downregulates p53 transcriptional activity, leading to stimulation of aerobic glycolysis and cell proliferation. Moreover, high expression of SIK3 stimulates mTOR-mediated aerobic glycolysis and cell proliferation of breast cancer cells. These findings suggest that SIK isoforms plays distinct role in aerobic glycolysis and cell growth of breast cancer, attenuated SIK1/p53 signaling suppresses oxidative phosphorylation and growth inhibitory effect in breast cancer cells, while enhanced SIK3/mTOR signaling potentiates aerobic glycolysis mediated cell growth in breast cancer cells.
盐诱导激酶（SIKs）属于 AMPK 相关家族激酶，SIK 家族的一种同工酶，SIK1 在各种类型的癌症中经常下调，有助于肿瘤发生。然而，其在乳腺癌中的确切作用及其相关的分子机制尚不清楚。在此，临床数据分析表明 SIK1 在乳腺癌组织中表达明显下调，并与乳腺癌的生存率密切相关。SIK1 具有促进氧化磷酸化的功能，这反过来又抑制乳腺癌细胞中的有氧糖酵解和细胞增殖。在机制上，SIK1 直接与 p53 相互作用并正向调节其转录活性，从而促进乳腺癌细胞中的氧化磷酸化。SIK1 的敲低会降低 p53 的转录活性，导致有氧糖酵解和细胞增殖的刺激。此外，SIK3 的高表达会刺激 mTOR 介导的乳腺癌细胞中的有氧糖酵解和细胞增殖。这些发现表明 SIK 同工酶在乳腺癌的有氧糖酵解和细胞生长中发挥不同的作用，减弱的 SIK1/p53 信号抑制乳腺癌细胞中的氧化磷酸化和生长抑制作用，而增强的 SIK3/mTOR 信号增强乳腺癌细胞中由有氧糖酵解介导的细胞生长。
