PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review)

Abstract

Renal cell carcinoma (RCC) accounts for over 90% of all renal malignancies, and mainly affects the male population. Obesity and smoking are involved in the pathogenesis of several systemic cancers including RCC. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway regulates cell growth, differentiation, migration, survival, angiogenesis, and metabolism. Growth factors, hormones, cytokine and many extracellular cues activate PI3K/AKT/mTOR. Dysregulation of this molecular pathway is frequently reported in human cancers including RCC and is associated with aggressive development and poor survival rate. mTOR is the master regulator of cell metabolism and growth, and is activated in many pathological processes such as tumour formation, insulin resistance and angiogenesis. mTOR inhibitors are used at present as drug therapy for RCC to inhibit cell proliferation, growth, survival, and the cell cycle. Temsirolimus and everolimus are two mTOR inhibitors that are currently used for the treatment of RCC. Drugs targeting the PI3K/AKT/mTOR signalling pathway may be one of the best therapeutic options for RCC.

Keywords: hyperactivation; mTOR inhibitors; renal cell carcinoma; risk factors; signalling pathway; tumour progression.

Figure 1

Activation of the AKT signalling pathway and biological effects [adapted from Araki et al (2003) and Meric-Bernstam and Gonzalez-Angulo (2009) (32,42)]. RTK, receptor tyrosine kinase; IRS, insulin receptor substrate; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homologue; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; PDK1, phosphoinositide-dependent-protein kinase 1; mTORC2. mammalian target of rapamycin complex 2.

Figure 2

The mTOR signalling pathway: Structure, biological effects, and inhibitors [adapted from Saxton and Sabatini (2017) and Laplante and Sabatin (2012) (47,48)]. mTOR, mammalian target of rapamycin; DEPTOR, DEP-domain containing mTOR-interacting protein; PRAS40, proline-rich AKT substrate 40-kDa; mLST8, lethal mammalian with sec-13 protein 8; Raptor, regulatory-associated protein of TOR; Rictor, rapamycin insensitive companion of mTOR; mSIN1, stress-activated protein kinase-interacting protein 1.