Low zinc environment induces stress signaling, senescence and mixed cell death modalities in colon cancer cells

Abstract

Currently it is not clear what type of the final cellular response (i.e. cell death modality or senescence) is induced upon chronic intracellular zinc depletion in colon cancer cells. To address this question, isogenic colon cancer lines SW480 and SW620 exposed to low zinc environment were studied over the period of 6 weeks. Low zinc environment reduced total as well as free intracellular zinc content in both cell lines. Decreased intracellular zinc content resulted in changes in cellular proliferation, cell cycle distribution and activation of stress signaling. In addition, colonocytes with low zinc content displayed increased levels of oxidative stress, changes in mitochondrial activity but in the absence of significant DNA damage. Towards the end of treatment (4th-6th week), exposed cells started to change morphologically, and typical markers of senescence as well as cell death appeared. Of two examined colon cancer cell lines, SW480 cells proved to activate predominantly senescent phenotype, with frequent form of demise being necrosis and mixed cell death modality but not apoptosis. Conversely, SW620 cells activated mostly cell death, with relatively equal distribution of apoptosis and mixed types, while senescent phenotypes and necrosis were present only in a small fraction of cell populations. Addition of zinc at the beginning of 4th week of treatment significantly suppressed cell death phenotypes in both cell lines but had no significant effect on senescence. In conclusion, presented results demonstrate variability of responses to chronic zinc depletion in colon cancer as modeled in vitro.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

“…Despite their tiny amount, micronutrients, i.e., vitamins and minerals, are essential for human health, exerting numerous functions, including antioxidant defence ranging from genome-related processes, such as DNA replication and repair, to metabolic processes and antioxidant defence [ 407 , 408 ]. Concerning the latter, the structural and functional roles of a few minerals such as zinc (Zn), selenium (Se), magnesium (Mg) copper (Cu) and manganese (Mn) is crucial ( Table 5 ) [ 409 , 410 , 411 , 412 , 413 , 414 , 415 , 416 , 417 , 418 , 419 , 420 ].…”

“…In vitro studies have shown that Zn deficiency is associated with an increased production of ROS, oxidative damage to DNA, proteins and lipids, destabilization of membrane structure, dysregulation of Zn-binding protein metallothionein [ 426 , 429 ]. For instance, in a colon cancer cell line [ 409 ] and dermal fibroblasts [ 410 ], Zn dysregulation promoted cellular senescence activating stress response and pro-apoptosis pathways. Some Zn-finger proteins and Zn-dependent enzymes, such as PATZ1 [ 430 ], ZKSCAN3 [ 431 ], ZHX3 [ 432 ], KLF4 [ 433 ] or Zfp637 [ 434 ] might be responsible for this Zn-mediated cellular senescence inhibition, reducing ROS production, DNA damage and telomere shortening ( Table 6 ) [ 430 , 431 , 432 , 433 , 434 , 435 , 436 , 437 ].…”

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

“…In colon cancer cells cultured in a low Zn environment for six weeks, morphological changes and also typical markers of senescence were detectable [213], while in contrast addition of Zn induced increased formation of ROS, causing senescence in vascular smooth muscle cells. Zn also decreased the cells’ antioxidative capacity by downregulation of catalase expression [214].…”

Solute carrier transporters: potential targets for digestive system neoplasms

“… 89 Low zinc environment was found to induce intracellular stress, and chronic zinc deficiency can cause changes in mitochondrial activity without significantly altering DNA damage and cell death, which thus induced cell senescence and growth inhibition. 90 Furthermore, zinc deficiency in cancer cells may lead to a shift toward phenotype of less malignancy, with presentation of enhanced apoptosis and reduced proliferation and invasion. 91 Depletion of intracellular zinc can reduce the migratory and invasive ability of cancer cells.…”