Autophagy Protects against Oxaliplatin-Induced Cell Death via ER Stress and ROS in Caco-2 Cells

Abstract

Oxaliplatin is included in a number of effective combination regimens used as first and subsequent lines of therapy for metastatic colorectal cancer. Accumulating evidence indicates that autophagy plays a significant role in response to cancer therapy. However, the role of autophagy in oxaliplatin-induced cell death remains to be clarified. In this study, we showed that oxaliplatin induced cell death and autophagy in Caco-2 colorectal cancer cells. The suppression of autophagy using either pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (ATG5 or Beclin1) enhanced the cell death and reactive oxygen species (ROS) production induced by oxaliplatin in Caco-2 cells. Blocking oxaliplatin-induced ROS production by using ROS scavengers (NAC or Tiron) decreased autophagy. Furthermore, numerous dilated endoplasmic reticula (ER) were present in oxaliplatin-treated Caco-2 cells, and blocking ER stress by RNA interference against candidate of metastasis-1 (P8) and C/EBP-homologous protein (CHOP) decreased autophagy and ROS production. Taken together, these data indicate that oxaliplatin activates autophagy as a cytoprotective response via ER stress and ROS in human colorectal cancer cells.

Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer

“…The findings of the present study are in line with a recent report in which OX was demonstrated to activate autophagy in colon cancer cells via the ER stress and ROS pathways, and inhibition of this autophagy increased cell death upon OX treatment in vitro (13). However, the current study performed an additional step to demonstrate the potential therapeutic efficiency and feasibility in vivo, using a combinational treatment strategy of an autophagy inhibitor and OX in a mouse model.…”

“…However, autophagy in cancer cells may promote cell survival by sustaining the cellular metabolism necessary for survival under hypoxic conditions and drug treatment, resulting in tumor growth and therapeutic resistance (8)(9)(10). In colon cancer, autophagy appears to favor cancer cell survival by protecting from tumor cell death caused by chemotherapy and radiotherapy (11)(12)(13)(14)(15). For example, it has been demonstrated that autophagy is responsible for the resistance of colon cancer cells to 5-fluorouracil (FU) treatment, as inhibition of autophagy enhances 5-FU-induced tumor cell apoptosis in vitro (11,12,15).…”

“…For example, it has been demonstrated that autophagy is responsible for the resistance of colon cancer cells to 5-fluorouracil (FU) treatment, as inhibition of autophagy enhances 5-FU-induced tumor cell apoptosis in vitro (11,12,15). In addition, OX can activate Enhancement of oxaliplatin-induced cell apoptosis and tumor suppression by 3-methyladenine in colon cancer cell autophagy via endoplasmic reticulum (ER) stress and the reactive oxygen species (ROS) pathway in human colon cancer cells to induce their resistance to OX treatment (13). Although the inhibition of autophagy can increase the sensitivity of colon cancer cells to OX treatment in vitro, the in vivo therapeutic effects of autophagy inhibition on tumor growth has yet to be investigated in animal models treated with OX.…”

Aldose Reductase Inhibitor Fidarestat as a Promising Drug Targeting Autophagy in Colorectal Carcinoma: a Pilot Study

“…The emerging role of autophagy has been well demonstrated in colorectal carcinoma in recent times (Yang et al, 2011;Shi et al, 2012;Han et al, 2014). Distinct patterns of expression of autophagy related proteins, viz.…”

“…Inflammation is a known hallmark of cancer; vascular insufficiency in tumors may lead to depletion of glucose and/or oxygen and thus contribute to increased reactive oxygen species production, extracellular acidosis in tumor microenvironment eventually resulting in autophagy, thereby implicating glucose depletion and or deprivation (GD) as a crucial trigger for autophagy (Bensaad et al, 2009;Du et al, 2013;Shoji-Kawata et al, 2013). My study hypothesis was that AR inhibition regulated autophagy in colorectal carcinoma.…”