Four neuroblastoma xenograft samples derived from cell lines with known N-myc gene copy number were also evaluated, as were 7 samples of non-small cell lung cancer (NSCLC) tumors with known Skp2 gene amplification.
Moreover, we also demonstrate that Skp2 has oncogenic potential by showing that Skp2 cooperates with H-Ras(G12V) to malignantly transform primary rodent fibroblasts as scored by colony formation in soft agar and tumor formation in nude mice.
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.
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.
Resistance to PI3K inhibitors correlated with the increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice.
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.
Immunohistochemically, increased CKS1B and SKP2, and attenuated p27(Kip1) were all associated with tumor multiplicity (P < 0.05) and increasing American Joint Committee on Cancer (AJCC) stage (P < 0.05).
We assessed the copy number and expression status of the possible target gene SKP2 for 5p amplification in cell lines and 33 primary stage II or III tumors of BTC.
Here, we show that ADAR2 editing rescue in astrocytomas prevents tumor growth in vivo and modulates an important cell cycle pathway involving the Skp2/p21/p27 proteins, often altered in glioblastoma.
In accord, knockdown of Skp2 suppressed the ability of MGC803 cells to form tumors and to metastasize to the lungs of mice, and the growth of established tumors, by inhibiting cell proliferation and enhancing cell apoptosis.
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.
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.
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.
Retroviral insertional activation of Fli-1 and Spi-1/PU.1, as well as loss of tumour suppressor genes such as p53 or p45 NFE2 have been shown to be critical for the induction and progression of Friend virus-induced erythroleukemias.