Abstract
Pharmacologically targeting activated STAT3 and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter, system xc-, contributes to redox balance and export of intracellularly produced glutamate in response to up-regulated glutaminolysis in cancer cells. We have previously shown that blocking STAT3/5 using the small molecule inhibitor, SH-4-54, which targets the SH2 domains of both proteins, increases xCT expression, thereby increasing system xc- activity in human breast cancer cells. The current investigation demonstrates that chronic SH-4-54 administration, followed by clonal selection of treatment-resistant MDA-MB-231 and T47D breast cancer cells, elicits distinct subtype-dependent effects. xCT mRNA and protein levels, glutamate release, and cystine uptake are decreased relative to untreated passage-matched controls in triple-negative MDA-MB-231 cells, with the inverse occurring in estrogen-responsive T47D cells. This “ying-yang” effect is linked with a shifted balance between the phosphorylation status of STAT3 and STAT5, intracellular ROS levels, and STAT5 SUMOylation/de-SUMOylation. STAT5 emerged as a definitive negative regulator of xCT at the transcriptional level, while STAT3 activation is coupled with increased system xc- activity. We propose that careful classification of a patient’s breast cancer subtype is central to effectively targeting STAT3/5 as a therapeutic means of treating breast cancer, particularly given that xCT is emerging as an important biomarker of aggressive cancers.
Highlights
Aggressive cancer cells adapt to increased levels of reactive oxygen species (ROS) that accompany their dysregulated metabolism by up-regulating the activity of the plasma membrane antiporter, system xc, which releases glutamate in exchange for cystine taken up from the extracellular environment
Phospho-STAT3 levels were significantly lower in MDA-MB-231 resistant clones relative to wild-type MDA-MB-231 cells, with the inverse occurring in T47D resistant clones in which phospho-STAT3 levels increased by approximately 3-fold relative to their respective untreated wild-type counterpart (Fig 1A)
In addition to the 95 kDa phospho-STAT5 band induced by PRL stimulation of T47D cells, a prominent 130 kDa and very weak 200 kDa band were detected after prolonged exposure (Fig 1C), which matched the banding pattern observed in MDA-MB-231 wild-type cells treated with PRL (Fig 1D)
Summary
Aggressive cancer cells adapt to increased levels of reactive oxygen species (ROS) that accompany their dysregulated metabolism by up-regulating the activity of the plasma membrane antiporter, system xc-, which releases glutamate in exchange for cystine taken up from the extracellular environment. Heterodimers of xCT4F2hc may complex with a variant of the CD44 cell adhesion molecule (CD44v) [3]. Of these components, xCT most prominently influences the function of system xc-, with high expression levels correlating with higher antiporter activity [2]. It has been suggested that insufficient xCT expression may sensitize cancer cells to ROS-mediated damage [3,4] and potentially curb their rapid proliferation [5] and metastatic potential [6]. It has been speculated that high levels of xCT may be an indicator of chemo- and radiation therapy resistance [7], making it a target for novel drug development
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