p66Shc—a longevity redox protein in human prostate cancer progression and metastasis

Abstract

Abstractp66Shc, a 66 kDa proto-oncogene Src homologous-collagen homologue (Shc) adaptor protein, is classically known in mediating receptor tyrosine kinase signaling and recently identified as a sensor to oxidative stress-induced apoptosis and as a longevity protein in mammals. The expression of p66Shc is decreased in mice and increased in human fibroblasts upon aging and in aging-related diseases, including prostate cancer. p66Shc protein level correlates with the proliferation of several carcinoma cells and can be regulated by steroid hormones. Recent advances point that p66Shc protein plays a role in mediating cross-talk between steroid hormones and redox signals by serving as a common convergence point in signaling pathways on cell proliferation and apoptosis. This article first reviews the unique function of p66Shc protein in regulating oxidative stress-induced apoptosis. Subsequently, we discuss its novel role in androgenregulated prostate cancer cell proliferation and metastasis and the mechanism by which it mediates androgen action via the redox signaling pathway. The data together indicate that p66Shc might be a useful biomarker for the prognosis of prostate cancer and serve as an effective target for its cancer treatment.

Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells

“…The protein level of p66Shc, a 66 kDa Src homologous-collagen homologue (Shc), is involved in regulating the proliferation of several carcinoma cells including PCa cells and can be up-regulated by steroids [20-23]. Fig.…”

“…Furthermore, by inhibiting AR signaling, AMD and DME may prevent the interaction of AR with p85α regulatory subunit of PI3K; which results in decreased Akt activation [39]. p66Shc, a 66 kDa oxidase, can up-regulate cell growth and is elevated in steroid-regulated carcinomas [20,23,40]. In PCa, p66Shc plays a role in mediating the cross-talk signal between steroids and tyrosine phosphorylation [40], which is involved in regulating cell proliferation and apoptosis [22,23,40,41].…”

ITGA2B and ITGA8 are predictive of prognosis in clear cell renal cell carcinoma patients

“…It is reported that one of the isoforms of SHC1 (p66 Shc ) can enhance proliferation of prostate cancer cells [40] and high expression of p66 Shc was found in primary breast tumors with high metastatic potential [41]. It also mediates steroid actin by regulating oxidative stress-induced apoptosis [42]. All the information suggests that SHC1 is a potential prognostic marker and cancer treatment target.…”

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

“…In fact, p66ShcA was shown to antagonize ERK activation via negative regulation of c-fos promoter activity (52) and to be mainly involved in oxidative stress signaling (53). Additionally, the role of p66ShcA in tumor metastasis is controversial (54,55). Therefore, the reduction of the p-ERK level after ShcA knockdown with the pan-ShcA siRNA was likely due to the depletion of p52/46ShcA.…”