Targeting autophagy for the treatment of cancer

Abstract Macroautophagy (herein termed autophagy) is evolutionarily highly conserved across eukaryotic cells and represents an intracellular catabolic process that targets damaged macromolecules and organelles for degradation. Autophagy is dysregulated in various human diseases including cancer. In addition, many drugs currently used for the treatment of cancer can engage autophagy, which typically promotes cancer cell survival by mitigating cellular stress. However, under certain circumstances activation of autophagy upon anticancer drug treatment can also trigger a lethal type of autophagy termed autophagic cell death (ACD). This may pave new avenues for exploiting the autophagic circuitry in oncology. This review presents the concept and some examples of anticancer drug-induced ACD.

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LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽

10.1038/s41389-021-00306-1 ◽

2021 ◽

Vol 10 (2) ◽

Author(s):

Yu Geon Lee ◽

Hui Won Kim ◽

Yeji Nam ◽

Kyeong Jin Shin ◽

Yu Jin Lee ◽

...

Keyword(s):

Cell Death ◽

Cell Growth ◽

Cell Survival ◽

Cancer Cell ◽

Stress Responses ◽

Molecular Mechanisms ◽

Tca Cycle ◽

Mitochondrial Matrix ◽

Mitochondrial Functions ◽

Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

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γ-Synuclein Promotes Cancer Cell Survival and Inhibits Stress- and Chemotherapy Drug-induced Apoptosis by Modulating MAPK Pathways

Journal of Biological Chemistry ◽

10.1074/jbc.m201650200 ◽

2002 ◽

Vol 277 (38) ◽

pp. 35050-35060 ◽

Cited By ~ 86

Author(s):

Zhong-Zong Pan ◽

Wendy Bruening ◽

Benoit I. Giasson ◽

Virginia M.-Y. Lee ◽

Andrew K. Godwin

Keyword(s):

Cell Survival ◽

Cancer Cell ◽

Drug Induced ◽

Chemotherapy Drug ◽

Mapk Pathways ◽

Cancer Cell Survival ◽

Induced Apoptosis

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Integrin Signaling in Cancer Cell Survival and Chemoresistance

Chemotherapy Research and Practice ◽

10.1155/2012/283181 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 49

Author(s):

Fawzi Aoudjit ◽

Kristiina Vuori

Keyword(s):

Cell Survival ◽

Cancer Cell ◽

Antibody Therapy ◽

Cancer Recurrence ◽

Critical Factor ◽

Cell Types ◽

Integrin Signaling ◽

Drug Induced ◽

Major Pathway ◽

Cancer Cell Survival

Resistance to apoptosis and chemotherapy is a hallmark of cancer cells, and it is a critical factor in cancer recurrence and patient relapse. Extracellular matrix (ECM) via its receptors, the integrins, has emerged as a major pathway contributing to cancer cell survival and resistance to chemotherapy. Several studies over the last decade have demonstrated that ECM/integrin signaling provides a survival advantage to various cancer cell types against numerous chemotherapeutic drugs and against antibody therapy. In this paper, we will discuss the major findings on how ECM/integrin signaling protects tumor cells from drug-induced apoptosis. We will also discuss the potential role of ECM in malignant T-cell survival and in cancer stem cell resistance. Understanding how integrins and their signaling partners promote tumor cell survival and chemoresistance will likely lead to the development of new therapeutic strategies and agents for cancer treatment.

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ATM inhibition drives metabolic adaptation via induction of macropinocytosis

10.1101/2020.04.06.027565 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chi-Wei Chen ◽

Raquel Buj ◽

Erika S. Dahl ◽

Kelly E. Leon ◽

Erika L. Varner ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Cancer Cell ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Dependent Manner ◽

Cancer Cell Survival ◽

Branched Chain

SummaryMacropinocytosis is a nonspecific endocytic process that enhances cancer cell survival under nutrient-poor conditions. Ataxia-Telangiectasia mutated (ATM) is a tumor suppressor that plays a role in cellular metabolic reprogramming. We report that suppression of ATM increases macropinocytosis in an AMPK-dependent manner to promote cancer cell survival in nutrient-poor conditions. Combined inhibition of ATM and macropinocytosis suppressed proliferation and induced cell death both in vitro and in vivo. Metabolite analysis of the ascites and interstitial fluid from tumors indicated decreased branched chain amino acids (BCAAs) in the microenvironment of ATM-inhibited tumors. Supplementation of ATM inhibitor-treated cells with BCAAs abrogated AMPK phosphorylation and macropinocytosis and rescued the cell death that occurs due to combined inhibition of ATM and macropinocytosis. These data reveal a novel molecular basis of ATM-mediated tumor suppression whereby loss of ATM promotes pro-tumorigenic uptake of nutrients to promote cancer cell survival and reveal a metabolic vulnerability of ATM-inhibited cells.

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