Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

Christopher Mccann,Emma M Kerr

doi:10.3390/cancers13133351

Abstract

Simple SummaryTumour cell metabolism is a dynamic and adaptive hallmark of cancer which enables cancer cells to survive, metastasise, proliferate and develop resistance to anti-cancer therapies. Here we review how metabolic reprogramming facilitates cancer cell survival, evasion of cell death processes such as apoptosis and facilitates the development of therapeutic resistance. We discuss how therapeutically-imposed metabolic dependencies can be rationally targeted to revert metabolic reprogramming from a supportive ‘friend’ to a fatal ‘foe’ of cancer cells.Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical “cell death” machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.

Highlights

We demonstrate the integral and powerful role the mitochondria play in maintaining cellular homeostasis, and how targeting or exploiting key functions of the mitochondria can revert this organelle from supportive Friend to lethal Foe
A wealth of drugs aimed at targeting mitochondrial systems such as BH3 mimetics and OXPHOS
BH3 mimetic in vitro to clinical efficacy is in part due to toxicity towards normal cells [174], but may be due to the often-overlooked metabolic implications of therapeutically disrupting mitochondrial function [30,167]

Summary

Introduction

Changes to the cancer metabolome is not a new concept, nearly 100 years ago Otto. Warburg reported that cancers had an enhanced avidity for glucose [1] and increased production of lactate [2], and these observations have since been confirmed across multiple cancer types [3] solidifying metabolic reprogramming as a key “Hallmarks of Cancer” [4,5]. Cytochrome-c pool is that which is responsible for electron transport and ROS management, i.e., serves a critical role in mitochondrial oxidative phosphorylation and ATP generation, but interestingly these processes are not significantly interrupted until the second wave of cytochrome-c is released, suggesting metabolic compensation is possible during incomplete MOMP. Ricci et al, revealed that following cytochrome-c release caspase-3 cleaves the p75 subunit (NDUFS1) of Complex I, resulting in further loss of mitochondrial membrane potential and mitochondrial integrity, production of ROS, plasma membrane damage and a fatal drop in ATP levels [36]. Caspases activate Endonuclease-G to facilitate irreparable DNA cleavage, and cleave core glycolytic enzymes, eliminating the ability for glycolysis to compensate for loss of ETC activity resulting in total bioenergetic collapse and toxic ROS generation Together, this promotes effective cancer cell death. As such, altered cancer metabolism has the potential to act as both a Friend and Foe to anti-cancer therapies, where the ultimate goal is to induce cell death

Driving Enhanced Cancer Growth Simultaneously Promotes Resistance to Death

Adaptations to Cellular Stress Prevent Metabolic Catastrophe and Death

Metabolites as Direct Mediators of Cancer Cell Death

Metabolism and Therapy Resistance

Findings

Summary