生物科学生物技术科技英语阅读精选(1) - 图文

required to maintain the full activities of the mitochondrial tricarboxylic acid cycle and oxidative phosphorylation after RAS activation66. Moreover, melanoma cell lines established from clinical samples depend on extracellular leucine, which can be rescued by autophagy activation68. Another remaining question in autophagy research is what triggers the autophagic response. Deprivation of essential amino acids activates autophagy through inhibition of the mTOR pathway. Notably, our group69 and others70 have shown that ammonia, a metabolic byproduct of amino acid catabolism, including glutaminolysis, acts as an autophagy inducer. Interestingly, this form of autophagy is

independent of the mTOR–unc-51-like protein kinase (ULK) pathway69. These observations suggest that autophagy induction is linked to either relative lack of or excess nitrogen, sensed by distinct mechanisms. How increased intracellular nitrogen is sensed and affects cancer development is still unclear. Considering that tumors with activated oncogenes, such as MYC or RAS, rely on glutaminolysis to generate bioenergetic fuel35, 71, we speculate that elevated autophagy in these

oncogene-driven tumors might be initiated through mechanisms sensing excess nitrogen.

As is clear from the above discussion, the role of autophagy in tumor initiation and progression is complex. Autophagy may suppress tumor growth in the

tumor-initiation stage, whereas in established tumors, it may fulfill metabolic needs of cancer cells during oncogene activation or nutrient limitation by providing a mechanism to recycle intracellular carbon and nitrogen. The cellular context of tumors (origin, stage and genetic makeup) influences the outcome of the autophagy response and must be considered when using autophagy modulation in cancer therapy.

Autophagy as a therapeutic target. Given the critical roles of autophagy in tumor progression and maintenance, various preclinical and clinical studies have been undertaken to develop therapeutic agents targeting autophagy. As most anticancer agents inevitably cause cellular stress, autophagy is often activated in cancer cells after drug treatment. Indeed, many therapies targeting growth factor signaling—either singly or in combinations

targeting two different pathways—lead to autophagy induction (Table 2). For example, several allosteric and catalytic inhibitors of mTOR, PI3K-AKT, and the tyrosine kinase signaling and activators of energy sensing pathway (e.g., 5′-AMP-activated protein kinase) induce autophagy in cells. Various agents targeting cellular processes such as histone deacetylation, proteasomal degradation, apoptosis and glycolysis have also been suggested to trigger autophagy (Table 2). It was originally proposed that autophagic cell death is part of the mechanism of action of anticancer drugs. Indeed, some combinatorial treatments with the above drugs have shown synergistic effects on the induction of cell death, which is reduced by knockdown of autophagy genes, suggesting that autophagy induced by chemotherapy contributes to its anticancer effect (Table 2). However, it has been suggested that the increased autophagy seen during anticancer drug treatment could also be a survival response of the dying cells rather than a cause of cell death72. As many autophagy inducers have shown limited success in clinical trials, it is necessary to assess the contribution of autophagy in the mechanisms of action of these drugs. Moreover, a growing body of

evidence indicates that stress-induced autophagy in tumor cells might drive cellular resistance to chemotherapy and facilitate tumor dormancy73, 74.

Table 2: Autophagy inducers and inhibitors for cancer treatment

In light of the above findings, inhibition of autophagy combined with conventional chemo/radiotherapy may be a useful approach clinically, and combination therapies with autophagy inhibitors and chemotherapeutics are being tested in clinical trials. A series of studies have reported that cancer therapeutics that induce autophagy synergize with autophagy inhibitors for anticancer effects both in many cancer cell lines and in xenograft models75, 76. The most common autophagy inhibitors used in clinical trials are chloroquine and hydroxychloroquine. These agents are registered antimalarial drugs that inhibit lysosomal acidification and impair autophagosome fusion with lysosomes and degradation77. Preclinical studies using a Myc-induced mouse lymphoma model suggest that inhibition of autophagy by treatment with

hydroxychloroquine increases cell death and substantially