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. 2018 Jan 25;9(2):118.
doi: 10.1038/s41419-017-0043-2.

Cell Death-Based Approaches in Treatment of the Urinary Tract-Associated Diseases: A Fight for Survival in the Killing Fields

Free PMC article

Cell Death-Based Approaches in Treatment of the Urinary Tract-Associated Diseases: A Fight for Survival in the Killing Fields

Diego Martin-Sanchez et al. Cell Death Dis. .
Free PMC article


Urinary tract-associated diseases comprise a complex set of disorders with a variety of etiologic agents and therapeutic approaches and a huge global burden of disease, estimated at around 1 million deaths per year. These diseases include cancer (mainly prostate, renal, and bladder), urinary tract infections, and urolithiasis. Cell death plays a key role in the pathogenesis and therapy of these conditions. During urinary tract infections, invading bacteria may either promote or prevent host cell death by interfering with cell death pathways. This has been studied in detail for uropathogenic E. coli (UPEC). Inhibition of host cell death may allow intracellular persistence of live bacteria, while promoting host cell death causes tissue damage and releases the microbes. Both crystals and urinary tract obstruction lead to tubular cell death and kidney injury. Among the pathomechanisms, apoptosis, necroptosis, and autophagy represent key processes. With respect to malignant disorders, traditional therapeutic efforts have focused on directly promoting cancer cell death. This may exploit tumor-specific characteristics, such as targeting Vascular Endothelial Growth Factor (VEGF) signaling and mammalian Target of Rapamycin (mTOR) activity in renal cancer and inducing survival factor deprivation by targeting androgen signaling in prostate cancer. An area of intense research is the use of immune checkpoint inhibitors, aiming at unleashing the full potential of immune cells to kill cancer cells. In the future, this may be combined with additional approaches exploiting intrinsic sensitivities to specific modes of cell death such as necroptosis and ferroptosis. Here, we review the contribution of diverse cell death mechanisms to the pathogenesis of urinary tract-associated diseases as well as the potential for novel therapeutic approaches based on an improved molecular understanding of these mechanisms.

Conflict of interest statement

The authors declare that they have no competing financial interests.


Fig. 1
Fig. 1
Cell death and survival during UTI. Factors modulating urothelial cell survival are summarized, but UPEC also interferes with cell death and survival in leukocytes, tubular epithelial cells, and others. a UPEC type 1 pili binds to uroplakin IIIa expressed in differentiated urothelial cells, allowing bacterial access to urothelial cells. This may trigger two different responses, depending on bacterial strain, stage of the infection, and the host cell context: (a) urothelial cell apoptosis or necrosis leading to tissue injury and shedding of injured cells and bacteria or (b) inhibition of host cell death favoring the survival of intracellular live bacteria. b Bacteria modulate cell survival through different mechanisms that may be strain-specific. UPEC may both promote (if HlyA is expressed) or inhibit inflammasome activation-dependent cell death. They may also promote an iron-dependent cell death that has not yet been characterized as ferroptosis
Fig. 2
Fig. 2
VHL mutations and RCC resistance to cell death. VHL is frequently mutated in hereditary and spontaneous RCC. This modifies the sensitivity to cell death through different pathways. Activation of HIF-1α and HIF-2α promotes the expression of intracellular and extracellular survival factors and of factors that promote angiogenesis and oxygen delivery, thus protecting from NK toxicity, hypoxia, and apoptosis. NFκB activation also protects from apoptosis, but creates an inflammatory milieu that sensitizes to necroptosis. The molecular basis for the increased sensitivity to ferroptosis remains currently unexplained

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