Autophagy delays apoptosis in renal tubular epithelial cells in cisplatin cytotoxicity

Abstract

One of the major side effects of cisplatin chemotherapy is toxic acute kidney injury due to preferential accumulation of cisplatin in renal proximal tubule epithelial cells and the subsequent injury to these cells. Apoptosis is known as a major mechanism of cisplatin-induced cell death in renal tubular cells. We have also recently demonstrated that autophagy induction is an immediate response of renal tubular epithelial cell exposure to cisplatin. Inhibition of cisplatin-induced autophagy blocks the formation of autophagosomes and enhances cisplatin-induced caspase-3, -6, and -7 activation, nuclear fragmentation and apoptosis. The switch from autophagy to apoptosis by autophagic inhibitors suggests that autophagy induction was responsible for a pre-apoptotic lag phase observed on exposure of renal tubular cells to cisplatin. Our studies provide evidence that autophagy induction in response to cisplatin mounts an adaptive response that suppresses and delays apoptosis. The beneficial effect of autophagy has a potential clinical significance in minimizing or preventing cisplatin nephrotoxicity.

BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway

“…We observed that autophagy was enhanced by etoposide. The upregulation of autophagy by chemotherapeutic drugs has already been described [42][43][44][45][46][47]. Chemotherapyinduced autophagy may promote cell resistance against it.…”

“…Doxorubicin-induced DNA damage stimulates cytoprotective autophagy through a PARP-1-dependent pathway [48]. Similarly, cisplatin-induced autophagy delays apoptosis in renal tubular epithelial cells [45] and tamoxifen and camptothecin-induced autophagy increases MCF7 breast carcinoma cell line viability [42,46]. Examples of autophagic cell death in response to chemotherapy were also described.…”

Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

“…In certain in vitro models, inhibition of autophagy increased cell death after injury whereas in others cell death was decreased. 12,13,22,28,32 It is recognized however that autophagy is induced during stress, and when stress persists, it may converge into apoptotic pathways. 30,31 This dual nature of autophagy and the increasing number of pathologies it is associated with highlight the importance of studying the regulation and effects of autophagy during kidney injury.…”

“…12,13,18,22,27 Under normal physiologic conditions, cells use autophagy to maintain homeostasis. If insufficient autophagy occurs, long-lived proteins and damaged organelles accumulate and cell death occurs.…”

“…[12][13][14][15] Autophagy, a physiologically regulated and evolutionarily conserved process, refers to an intracellular degradation system in which cytoplasmic components, such as damaged organelles, longlived proteins, protein aggregates, and other macromolecules, are directed to the lysosome. 16 -19 Autophagy (also referred to as macroautophagy) begins with the formation of an initiation membrane (vesicle nucleation) that sequesters cytoplasmic components as it expands (vesicle elongation); finally, the edges fuse to form a double-membraned vesicle called autophagosome.…”