Resistance to PI3K inhibitors correlated with the increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice.
Our data showed that SKP2 levels were significantly increased in HCC cell lines and HCC tissues rather than corresponding normal liver tissues, and augmented SKP2 levels were statistically correlated with tumor grade, size and metastases.
In histology subgroup analysis, differences in Skp2 protein expression were observed in patients with LUAD, based on sex, differentiation, smoking history, stage, lymph node metastasis and tumor diameter (P<0.05), but not in patients with LUSC except for smoking status.
Transcript expression of SKP2, a SCF<sup>SKP</sup> component, was elevated in RB1-defective TNBCs, suggesting that in these tumours, SKP2 activity might buffer the effects of RB1 dysfunction.
The present results revealed that genistein exerted its tumor suppressor effect at least partially via inhibition of Skp2 and promotion of its downstream targets p21 and p27.
Skp2 (Fbxl1) directly binds to the tumor suppressor p27 in the context of the SCF<sup>Skp2</sup> E3 ubiquitin ligase to ubiquitylate and target-phosphorylated p27 for proteasomal degradation.
In a xenograft mouse model implanted with PC-3-Pa cells, LJ-2618 (3 or 10 mg/kg) effectively inhibited tumor growth with the enhancement of Skp2 degradation and induction of p27 expression in tumor tissues.
Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2.
Finally, we describe how the MYC/CDK2/p27/SKP2 axis impacts on tumor development and discuss possible ways to interfere therapeutically with this system to improve cancer treatment.
High p53-, phospho (p)-Rb-, SKP2-, cyclin D1-, and p-c-myc-positive rates were correlated with HPV-negative tumors, whereas high p16- and p27-positive rates were associated with HPV-positive tumors.
Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation.
S-phase kinase-associated protein 2 (SKP2) (also known as FBXL1) is often overexpressed in human cancers, and functions as an oncogenic E3 ligase to degrade tumor suppressor gene products.
Tumor samples were collected to examine the association between the expression of S-phase kinase-associated protein 2 (SKP2) and prognosis in cervical cancer.
Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice.
S phase kinase-associated protein 2 (Skp2) has been shown to be required for spontaneous tumor development that occurs in the retinoblastoma protein (pRb) deficient mice.
The results established a paradigm whereby systemic Akt1 inhibition is sufficient to regress tumors that are not driven by Akt activation and a mechanism of cell survival by Skp2.
Overexpression of Skp2 and loss of CDKN1B (p27) was strongly associated with aggressive tumor behavior and poor clinical outcome in a variety of cancers, including colorectal cancer.
IHC showed SKP2 to be more highly expressed in estrogen receptor α (ERα)-negative breast cancers and demonstrated that triple-negative tumors were more likely to have high expression of SKP2 than were non-triple negative, ERα-negative tumors.
This reciprocal regulation between DAB2IP and Skp2 protein represents a unique homeostatic balance between tumor suppressor and oncoprotein in normal prostate epithelia, which is apparently altered in cancer cells.
Furthermore, we found that depletion of Skp-2 caused a dramatic cell cycle arrest, followed by massive apoptotic cell death, and eventually resulted in a significant decrease in growth, viability and tumor formation in renal cancer cell lines studied.