Cardiomyocyte autophagy and cancer chemotherapy

Abstract

Autophagy, an evolutionally conserved process of controlled cellular cannibalization, plays a vital role in cardiac physiology. Perturbations in cardiomyocyte autophagy contribute to the pathogenesis of a wide range of cardiac diseases, many of which culminate in heart failure. With recent advances in cancer chemotherapy and consequent improvements in cancer survival, drug-induced toxicity to the heart has assumed greater importance. As a number of prominent cellular pathways are critical to the survival of both tumor cells and heart cells, it comes as little surprise that therapies targeting those pathways have consequences in both tissues. Little is known presently about cardiomyocyte autophagy, a prominent cellular response to stress, in the setting of chemotherapy, but preliminary evidence suggests an important and context-dependent role. Dissecting the role of autophagy in "onco-cardiology" will likely yield insights into mechanisms underlying cardiomyopathy and may lead to novel means to protect the myocardium from chemotherapy-induced injury. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".

Keywords: Autophagy; Cardiomyocyte; Cardiomyopathy; Chemotherapy.

Figure 1. Regulation of autophagy

Autophagy starts with nucleation of an intracellular membrane structure termed the phagophore. Elongation and closure of the phagophore leads to the formation of the autophagosome which harbors cytoplasmic material, such as protein aggregates or a mitochondrion. Subsequent fusion of the autophagosome with a lysosome (maturation) leads to degradation of the autophagosomal cargo and inner membrane by lysosomal enzymes. Initiation of the autophagic cascade is regulated by multiple elements, including mTORC1 and AMPK. Beclin1, a core component of the class III phosphatidylinositol 3-kinase VPS34 complex, can be sequestered by its binding to BCL-2 or BCL-X_L, leading to inhibition of autophagy. Autophagosome maturation can also be regulated. TFEB, a transcription factor that governs lysosomal biogenesis as well as expression of genes coding for multiple autophagic proteins, promotes autophagic flux. Binding of Beclin1 to UVRAG promotes autophagosome maturation, while the Rubicon-Beclin1-UVRAG complex acts oppositely.

Figure 2. Possible roles of autophagy in chemotherapy-induced cardiomyopathy

A. Chemotherapies (e.g. imatinib, sunitinib) induce cellular stress, such as hypoxia, ER stress, organelle damage, etc., which trigger autophagy. Autophagy functions as a protective mechanism in both cancer cells and cardiomyocytes. B. Anti-cancer agents inhibit autophagy directly (e.g. chloroquine) in both cancer cells and cardiomyocytes, causing damage to both cell types. C. Anti-cancer agents (e.g. possibly doxorubicin) have no clear effect on cancer cell autophagy but might block autophagy in cardiomyocytes, promoting cardiomyopathy. D. anticancer agents (e.g. possibly doxorubicin) might stimulate maladaptive autophagy in cardiomyocytes, promoting cardiomyopathy.