Das Shreya, Shukla Nidhi, Singh Shashi Shekhar, Kushwaha Sapana, Shrivastava Richa
Department of Pharmacy, Birla Institute of Technology and Sciences (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Apoptosis. 2021 Oct;26(9-10):512-533. doi: 10.1007/s10495-021-01687-9. Epub 2021 Sep 12.
The mechanisms of two programmed cell death pathways, autophagy, and apoptosis, are extensively focused areas of research in the context of cancer. Both the catabolic pathways play a significant role in maintaining cellular as well as organismal homeostasis. Autophagy facilitates this by degradation and elimination of misfolded proteins and damaged organelles, while apoptosis induces canonical cell death in response to various stimuli. Ideally, both autophagy and apoptosis have a role in tumor suppression, as autophagy helps in eliminating the tumor cells, and apoptosis prevents their survival. However, as cancer proceeds, autophagy exhibits a dual role by enhancing cancer cell survival in response to stress conditions like hypoxia, thereby promoting chemoresistance to the tumor cells. Thus, any inadequacy in either of their levels can lead to tumor progression. A complex array of biomarkers is involved in maintaining coordination between the two by acting as either positive or negative regulators of one or both of these pathways of cell death. The resulting crosstalk between the two and its role in influencing the survival or death of malignant cells makes it quintessential, among other challenges facing chemotherapeutic treatment of cancer. In view of this, the present review aims to highlight some of the factors involved in maintaining their diaphony and stresses the importance of inhibition of cytoprotective autophagy and deletion of the intermediate pathways involved to facilitate tumor cell death. This will pave the way for future prospects in designing drug combinations facilitating the synergistic effect of autophagy and apoptosis in achieving cancer cell death.
在癌症背景下,自噬和凋亡这两种程序性细胞死亡途径的机制是广泛关注的研究领域。这两种分解代谢途径在维持细胞以及机体稳态方面都发挥着重要作用。自噬通过降解和清除错误折叠的蛋白质及受损细胞器来促进这一过程,而凋亡则在响应各种刺激时诱导典型的细胞死亡。理想情况下,自噬和凋亡都具有肿瘤抑制作用,因为自噬有助于清除肿瘤细胞,而凋亡可阻止其存活。然而,随着癌症的发展,自噬会表现出双重作用,即通过增强癌细胞在缺氧等应激条件下的存活能力,从而促进肿瘤细胞的化疗耐药性。因此,它们任何一方水平的不足都可能导致肿瘤进展。一系列复杂的生物标志物通过作为这两种细胞死亡途径中一种或两种的正调控或负调控因子,参与维持两者之间的协调。两者之间由此产生的相互作用及其对恶性细胞存活或死亡的影响,使其成为癌症化疗面临的诸多挑战中至关重要的一点。有鉴于此,本综述旨在强调一些参与维持它们之间和谐关系的因素,并强调抑制细胞保护性自噬以及消除相关中间途径以促进肿瘤细胞死亡的重要性。这将为未来设计药物组合铺平道路,这些药物组合有助于自噬和凋亡的协同作用以实现癌细胞死亡。