Abstract
The phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of the rapamycin (mTOR)-signaling pathway has been suggested to have connections with the malignant transformation, growth, proliferation, and metastasis of various cancers and solid tumors. Relevant connections between the PI3K/Akt/mTOR pathway, cell survival, and prostate cancer (PC) provide a great therapeutic target for PC prevention or treatment. Recent studies have focused on small-molecule mTOR inhibitors or their usage in coordination with other therapeutics for PC treatment that are currently undergoing clinical testing. In this study, the function of the PI3K/Akt/mTOR pathway, the consequence of its dysregulation, and the development of mTOR inhibitors, either as an individual substance or in combination with other agents, and their clinical implications are discussed. The rationale for targeting the PI3K/Akt/mTOR pathway, and specifically the application and potential utility of natural agents involved in PC treatment is described. In addition to the small-molecule mTOR inhibitors, there are evidence that several natural agents are able to target the PI3K/Akt/mTOR pathway in prostatic neoplasms. These natural mTOR inhibitors can interfere with the PI3K/Akt/mTOR pathway through multiple mechanisms; however, inhibition of Akt and suppression of mTOR 1 activity are two major therapeutic approaches. Combination therapy improves the efficacy of these inhibitors to either suppress the PC progression or circumvent the resistance by cancer cells.
Highlights
Prostate cancer (PC) represents the second highest form of cancer-related mortality in men [1]
Multiple studies exhibited that the phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR pathway could potentially play an important role in prostate cancer (PC) as a therapeutic target and/or a predictive biomarker for the onset, progression, and behavior of the disease
The TGF-β/PI3K/Akt-mTOR-NFκB transduction pathway has been confirmed to be activated in PC
Summary
Prostate cancer (PC) represents the second highest form of cancer-related mortality in men [1]. Several other chemotherapeutic agents, including cabazitaxel, sipuleucel-T, and alpharadin, as well as the Food and Drug Administration (FDA)-approved androgen synthesis inhibitors abiraterone acetate (new-generation antiandrogens) and enzalutamide (the novel androgen receptor (AR) inhibitor), are regularly prescribed for PC treatment, depending on patient conditions and the extent and location of the disease [7] While these therapies provide clinical benefits for PC, the survival rate of patients remains poor. Data has shown that irregularity in the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR-signaling pathway has been implicated in various human cancer types including PC [9]. The PI3K/Akt/mTOR pathway is analogous with cell growth, development, proliferation, metastasis, malignant transformations, tumor progression, therapeutic resistance, and apoptosis [10]. Binding protein 1 (4E-BP1) phosphorylation and activation, resulting in the elevation of the translation rate of several mRNAs that play a role in cell growth, metabolism, and oncogenic transformation [18]
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