The Role of p66Shc in Cancer: Molecular Mechanisms and Therapeutic Implications

Abstract

p66Shc is a redox-sensitive and pro-apoptotic adaptor protein that regulates oxidative stress and mitochondrial apoptosis. It is the largest of three isoforms encoded by the proto-oncogene ShcA (Src collagen homologue A). Members of the ShcA family are capable of recruiting various signalling molecules and are involved in several cellular pathways, including proliferation, growth and survival. Increasing evidence highlights the p66Shc role in various tumourigenic processes, such as cell expansion, progression, metastasis and metabolic reprogramming. This review summarises current knowledge on the role of p66Shc in cancer, explains the molecular mechanisms underlying the effects of this protein, and considers therapeutic prospects aimed at targeting it. Emerging therapeutic strategies, including small-molecule inhibitors and gene-editing approaches, are discussed alongside challenges in clinical translation.

Keywords: cancer; p66Shc; reactive oxygen species; signalling pathway.

FIGURE 1

Schematic structure of Shc proteins: P66Shc, p52Shc and p46Shc isoforms. Each isoform is conserved by distinct functional domains, including PTB, CH1 and SH2; the cytochrome C binding domain is found in p52Shc and p66Shc; however, p66Shc also represents CH2. The CH1 domain is phosphorylated in response to activated receptor tyrosine kinases, which promote mitogenic responses. In contrast, phosphorylation and acetylation of the CH2 domain trigger oxidative responses. Phosphorylation sites represented (P). Created with BioRender.com [1].

FIGURE 2

Pathway interactions involving p66Shc: This diagram represents key signalling pathways, including the PI3K/Akt pathway, MAPK/ERK pathway and NF‐κB pathway, which are influenced by p66Shc and their interplay with apoptotic mechanisms. Upon activation by RTKs and TGF‐β, p66Shc facilitates critical phosphorylation events that drive cellular processes, including mRNA translation, lipid synthesis, cell proliferation and EMT. Additionally, it reveals how p66Shc plays as a hub connecting these pathways, promoting tumoral migration and metastasis while modulating apoptotic signals through interactions with BCL‐2 family proteins and Caspases. Additionally, the crosstalk between these pathways highlights the complexity of tumour biology. Created with BioRender.com [3, 4, 10].

FIGURE 3

p66Shc's roles in cancer and related diseases: Adaptive or variable functions. This schematic illustrates the structural domains of p66Shc and their activation by various stress signals, including ROS and RTKs. It depicts the dual roles of p66Shc in cellular physiology: (1) as a tumour suppressor—mediating mitochondrial ROS production and Cytc release to promote apoptosis in BC and CLL, with this function being potentiated by HDAC inhibitors; and (2) as an oncoprotein—activating proliferative and metastatic pathways via PI3K/Akt, MAPK/ERK and STAT3 signalling cascades in HCC, PCa and leukaemia. The figure further highlights the impact of pharmacological modulation, such as HDAC inhibitors in CLL and Dioscorea zingiberensis (DZ) in diabetic nephropathy (DN), where p66Shc inhibition attenuates NLRP3 inflammasome activity and oxidative stress, potentially influencing cancer‐related comorbidities, including HCC. Created with BioRender.com [138, 139, 140].