Peroxiredoxin 2 specifically regulates the oxidative and metabolic stress response of human metastatic breast cancer cells in lungs

Abstract

Little is known about metastatic pathways that are specific to the lung rather than other organs. We previously showed that antioxidant proteins such as peroxiredoxins were specifically upregulated in lung metastatic breast cancer cells. We hypothesize that cancer cells that live under aerobic conditions, as might be the case in lungs, protect themselves against the damage caused by reactive oxygen species (ROS). To examine this hypothesis, we studied the role of peroxiredoxin-2 (PRDX2) in lung vs bone metastasis formation. A metastatic variant of MDA-MB-435 breast cancer cells that specifically metastasize to lungs (435-L3) was transduced with short hairpin RNAs to specifically silence PRDX2. Conversely, a bone metastatic variant of MDA-MB-231 cells (BO2) was stably transfected to overexpress PRDX2. The 435-L3 cells silenced for PRDX2 were significantly more sensitive to H(2)O(2)-induced oxidative stress than the parental and scrambled transfected cells. BO2/PRDX2 cells produced less ROS than BO2/green fluorescent protein control cells under oxidative stress. Moreover, PRDX2 knockdown inhibited the growth of 435-L3 cells in the lungs, whereas lymph node metastasis remained unaffected. In contrast, PRDX2 overexpression in bone metastatic BO2 breast cancer cells led to drastic inhibition of the skeletal tumor burden and reduction of bone destruction. Furthermore, PRDX2 expression in breast cancer cells was associated with a glucose-dependent phenotype, different from bone metastatic cells. Overall, our results strongly suggest that PRDX2 is a targetable 'metabolic adaptor' driver protein implicated in the selective growth of metastatic cells in the lungs by protecting them against oxidative stress.

Functional roles of MMP14 and MMP15 in early postnatal mammary gland development

“…We are, however, unable to assess the catalytic activity of MMP15 per se as specific antibodies capable of distinguishing between the pro-and active forms of the enzyme have not been generated. Nevertheless, it is intriguing that the breast cancer-associated transcripts γ-synuclein (Ahmad et al, 2007) and peroxiredoxin 2 (Stresing et al, 2013) are among the most significantly affected (∼5-fold increase and ∼7-fold decrease, respectively).…”

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

“…Another antioxidant mechanism found to play a role in lung metastasis is the upregulation of peroxiredoxins, small antioxidant proteins that shuttle electrons in order to reduce hydrogen peroxide. Stresing and colleagues discovered that lung metastases originating from breast tumors specifically upregulate the expression of peroxiredoxin 2 (PRDX2) (Stresing et al, 2013). Increased expression of PRDX2 facilitated survival in the lung where pro-oxidative stress is particularly prevalent (Figure 2).…”

PRDX2 protects hepatocellular carcinoma SMMC-7721 cells from oxidative stress

“…Similar to PRDXs, PRDX2 has been demonstrated to form disulfide-linked homodimers during its catalytic cycle (2). The expression of PRDX2 is unregulated in breast cancer, cervical cancer and colorectal cancer (3)(4)(5)(6). By contrast, silencing of PRDX2 occurs in acute myeloid leukemia and malignant melanomas (7,8).…”

“…The pro-tumorigenic role of PRDX2 may be attributed to, at least partially, protecting cells from oxidative stress (3)(4)(5)(6). Under oxidative stress, reactive oxygen species (ROS) also contribute to tumor necrosis factor-α (TNF-α)-induced cell death (9).…”