Abstract
The expression of IκB kinase β (IKKβ) promotes the growth of breast cancer cells. Meanwhile, IKKβ mediates the phosphorylation and subsequent degradation of arrest-defective protein 1 (ARD1). However, the relationship between IKKβ and ARD1 in the occurrence of breast cancer has not been reported. In this study, we found that IKKβ not only acts directly on mammalian target of rapamycin (mTOR) activity but also indirectly acts on mTOR activity through posttranscriptional modification of ARD1, thereby effectively promoting the growth of breast cancer cells. ARD1 prevents mTOR activity and breast cancer cell growth by stabilizing tuberous sclerosis complex 2 (TSC2) to induce autophagy. Moreover, acetylation of heat shock protein 70 (Hsp70) also contributes to ARD1-mediated autophagy. Therefore, upstream IKKβ can further promote the occurrence of breast cancer by mediating the function of ARD1.
Highlights
IκB kinase β (IKKβ) is an integral part of the IKK complex
IKKβ-mediated arrest-defective protein 1 (ARD1) degradation is required for IKKβinduced growth of breast cancer cells We first examined protein expression after tumor necrosis factor α (TNFα) treatment
In a xenograft mouse model, ARD1 overexpression decreased xenograft breast cancer growth[18], indicating that ARD1 is a suppressor of breast tumorigenesis
Summary
IκB kinase β (IKKβ) is an integral part of the IKK complex. The complex consists of IKKα, IKKβ, and a regulatory subunit, IKKγ1–4. IKKβ is a major downstream kinase in the tumor necrosis factor α (TNFα) pathway[5] and can be activated by inflammatory signals such as TNFα or lipopolysaccharide (LPS). Activated IKKβ can promote the nuclear translocation of nuclear factor κB (NF-κB) by phosphorylation and degradation of IκBα1,4,6. NF-κB activates its target genes to initiate a series of functions. Constitutive activation of IKK and NF-κB family members contributes to the development of breast cancer[3]. Previous studies showed that IKKβ promoted the development of breast carcinoma by phosphorylating two tumor suppressor factors, forkhead box O3a (FOXO3a) and tuberous sclerosis complex 1 (TSC1).
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