Prostate cancer cells at a therapeutic gunpoint of the autophagy process

Abstract

In a normal prostate, the process of controling cell death is essential to maintain tissue homeostasis and its inhibition may lead to the development of cancer. Androgen receptor signaling plays pivotal roles in the prostate development and homeostasis as well as in the progression of prostate cancer. The main treatment for prostate cancer is a combination of androgen deprivation therapy (ADT) using anti-androgens and docetaxil administration. However, ADT eventually fails due to a pathological unbalance of cell death processes, in particular apoptosis and autophagy. As a result prostate tumors may re-grow and progress into the castration resistant stage. The role of autophagy in tumorigenesis is complex and it could be a double-edged sword process, as autophagy defects promote cancer progression in association with various dangerous cellular processes, while functional autophagy enables cancer cell survival under stress and likely contributes to the resistance of treatment. Autophagy is often impaired in prostate cancer, due to either activation of the Akt/mTOR pathway, which normally inhibits autophagy, or through allelic loss of Beclin-1 (BECN1), an essential autophagy gene. In particular, elucidating the interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets and to develop synthetically lethal treatment strategies that preferentially target cancer cells, while sparing normal tissues.

PKM2 Knockdown Induces Autophagic Cell Death via AKT/mTOR Pathway in Human Prostate Cancer Cells

“…In the cellular environment, PKM2 is associated with protein kinase B (Akt)/mechanistic or mammalian target of rapamycin (mTOR) signaling pathway [33], which regulates numerous cellular processes, including cell growth and survival, cell cycle progression, protein synthesis, and angiogenesis [34]. Activation of the Akt/mTOR pathway impairs autophagy in prostate cancer cells [34].…”

“…In the cellular environment, PKM2 is associated with protein kinase B (Akt)/mechanistic or mammalian target of rapamycin (mTOR) signaling pathway [33], which regulates numerous cellular processes, including cell growth and survival, cell cycle progression, protein synthesis, and angiogenesis [34]. Activation of the Akt/mTOR pathway impairs autophagy in prostate cancer cells [34]. Autophagy is a well-regulated homeostatic mechanism characterized by the collection of the cytoplasmic machinery into autophagosomes, followed by its lysosomal proteolytic digestion and recycling to maintain cellular growth [35].…”

“…Autophagy is highly regulated by the kinase mTOR. In cancer cells, overexpressed PKM2 activates mTORC1 by phosphorylating its substrate AKT1 substrate 1 (AKT1S1), which in turn accelerates autophagy inhibition and oncogenic growth, leading to poor patient outcomes [34,37].…”

Active Ingredients from Euodia ruticarpa Steam Distilled Essential Oil Inhibit PC-3 Prostate Cancer Cell Growth via Direct Action and Indirect Immune Cells Conditioned Media In Vitro

“…However, testosterone, a hormone produced in the testicles, may further stimulate prostate hyperplasia in some patients [3]. Most advanced prostate cancer patients evolve an uncontrollable castration-resistant prostate cancer (CRPC), resulting in scantiness of hormones in the body and increasing the difficulty for prostate cancer treatments [4]. Therefore, it is more and more important to research a new and curative treatment program for prostate cancer through modulating immune balance with low cytotoxic and effective compounds from different food and herb materi-the number of T lymphocytes (CD4 + and CD8 + ) in BALB/c CT 26 tumor-bearing mice [25].…”

Hsp90 Relieves Heat Stress-Induced Damage in Mouse Kidneys: Involvement of Antiapoptotic PKM2-AKT and Autophagic HIF-1α Signaling

“…Light chain 3 (LC3), is essential for autophagy and serves as a vital component in monitoring autophagy and visualizing autophagosomes in vivo [15]. Pyruvate kinase M2 isoform (PKM2), a rate-limiting terminal glycolytic enzyme, catalyzes the last step of glycolysis, and recent studies have reported that PKM2 is associated with the Akt signal pathway, which regulates cell survival and apoptosis [16,17]. Meanwhile, many cellular signals have been reported to be involved in the regulation of autophagy, including the Akt (protein kinase B)-mTOR (mammalian target of rapamycin) pathway [18,19].…”