Abstract
The Map kinase Activating Death Domain containing protein (MADD) isoform of the IG20 gene is over-expressed in different types of cancer tissues and cell lines and it functions as a negative regulator of apoptosis. Therefore, we speculated that MADD might be over-expressed in human breast cancer tissues and that MADD knock-down might synergize with chemotherapeutic or TRAIL-induced apoptosis of breast cancer cells. Analyses of breast tissue microarrays revealed over-expression of MADD in ductal and invasive carcinomas relative to benign tissues. MADD knockdown resulted in enhanced spontaneous apoptosis in human breast cancer cell lines. Moreover, MADD knockdown followed by treatment with TRAIL or doxorubicin resulted in increased cell death compared to either treatment alone. Enhanced cell death was found to be secondary to increased caspase-8 activation. These data indicate that strategies to decrease MADD expression or function in breast cancer may be utilized to increase tumor cell sensitivity to TRAIL and doxorubicin induced apoptosis.
Highlights
Map kinase Activating Death Domain containing protein (MADD), a splice variant of the IG20 gene, is essential for cancer cell survival and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment
We have demonstrated that the pro-survival protein MADD, an isoform of the IG20 gene, is significantly over expressed in breast tissues containing ductal carcinoma in situ (DCIS) and invasive breast cancer, as well as in the three evaluated breast cancer cell lines
We confirmed the ability to down regulate MADD expression using small hairpin-RNAs (shRNAs), which resulted in spontaneous apoptosis that was further augmented by treatment with TRAIL or doxorubicin, a standard chemotherapeutic agent used in advanced invasive breast cancer patients
Summary
Map kinase Activating Death Domain containing protein (MADD), a splice variant of the IG20 gene, is essential for cancer cell survival and confers resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment. TRAIL normally binds to death receptors-4 (DR4) and -5 (DR5) on cancer cells resulting in DR oligomerization and subsequent recruitment of the Fas associated Death Domain containing protein (FADD) and procaspase-8 to DRs [1,2,3]. The ability of doxorubicin to synergize TRAIL-induced apoptosis demonstrates a critical interplay between the extrinsic and the intrinsic apoptotic pathways [7,8,9,10] that can be exploited to more effectively kill cancer cells while reducing the undesirable side effects of high dose chemotherapy. Development of chemotherapy and TRAIL resistance due to the expression of different anti-apoptotic proteins remains a major challenge
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