Depletion of dAKAP1–protein kinase A signaling islands from the outer mitochondrial membrane alters breast cancer cell metabolism and motility

Abstract

Breast cancer screening and new precision therapies have led to improved patient outcomes. Yet, a positive prognosis is less certain when primary tumors metastasize. Metastasis requires a coordinated program of cellular changes that promote increased survival, migration, and energy consumption. These pathways converge on mitochondrial function, where distinct signaling networks of kinases, phosphatases, and metabolic enzymes regulate these processes. The protein kinase A-anchoring protein dAKAP1 compartmentalizes protein kinase A (PKA) and other signaling enzymes at the outer mitochondrial membrane and thereby controls mitochondrial function and dynamics. Modulation of these processes occurs in part through regulation of dynamin-related protein 1 (Drp1). Here, we report an inverse relationship between the expression of dAKAP1 and mesenchymal markers in breast cancer. Molecular, cellular, and in silico analyses of breast cancer cell lines confirmed that dAKAP1 depletion is associated with impaired mitochondrial function and dynamics, as well as with increased glycolytic potential and invasiveness. Furthermore, disruption of dAKAP1-PKA complexes affected cell motility and mitochondrial movement toward the leading edge in invasive breast cancer cells. We therefore propose that depletion of dAKAP1-PKA "signaling islands" from the outer mitochondrial membrane augments progression toward metastatic breast cancer. Approximately one in eight women are diagnosed with breast cancer. Recent advances in detection and diagnosis, when combined with precision therapies that tailor drug treatment to the genetic profile of patients increase the likelihood of good prognoses (1). Nonetheless, 5-year survival rates plummet to 22% for patients with metastatic (stage IV) disease (2). Elucidating the molecular mechanisms that underlie the transition to metastatic breast cancers remains challenging, yet it is a necessary prelude to the development of new therapies. The onset of metastasis is often marked by a cellular reprogramming paradigm that alters gene expression patterns, migration competency, and metabolism (3). This paradigm shares many features with the developmental process known as the epithelial-to-mesenchymal transition (EMT) 6 (4-6). Furthermore, highly proliferative cancer cells often exhibit enhanced glycolytic capacity (3, 7). Recent studies show that both glycolysis and oxidative metabolism at mitochondria are critical for the progression to metastasis and the survival of cancer cells as they establish distant tumors (8-10). Such multifaceted control of tumor cell metabolism highlights the importance of mitochondrial signaling events during metastatic tumor progression. Bioinformatic analyses of mRNA and protein data sets have identified predictive elements of tumor progression that change during EMT and metastasis (11, 12). Many of these altered proteins regulate processes such as cytoskeletal remodeling, cell adhesion, and cellular metabolism, which are critical to tumor cell migration and survival (11). One class of...

A-Kinase Anchoring Protein 1: Emerging Roles in Regulating Mitochondrial Form and Function in Health and Disease

“…Moreover, mitochondrial fission resulting from AKAP1 downregulation may increase the efficiency of mitochondrial transportation toward the high energy demanding leading edge of metastatic cells. Thus, reduced AKAP1 expression can be viewed as a biochemical switch toward increased breast cancer metastasis [56]. While this study may appear to be contradictory to studies where increased AKAP1 has been viewed as a "bad" sign for cancer patients, a closer look opens up very fascinating discussions about the dynamic changes adopted by cancer cells when transitioning at different disease stages.…”

“…Several recent studies have suggested that the role of AKAP1 in cancer is complicated due to the heterogeneous nature of cancer cells in different stages of tumor growth and metastasis. While one study suggested AKAP1 inhibits cancer cell invasiveness [56], other studies have reported a poorer prognosis with higher AKAP1 expression [57,58].…”

“…Conversely, reduction of AKAP1 expression was found to be an indicator of malignancy transition in breast cancer progression. Reduced levels of AKAP1 were observed in invasive breast cancer cell lines, as well as in patient biopsies taken from sites of metastasis [56]. The decreased AKAP1 level is thought to be associated with metabolic reprogramming from oxidative phosphorylation to glycolysis as the cancer cell required faster energy production.…”

“…In summary, we can perhaps picture the following scenario for cancer progression: at the tumor stroma, the cells metabolically favor glycolysis and fuel the epithelial cancer cells, which adopt high OXPHOS cellular respiration (high AKAP1) to promote tumor growth [54,55,59]. During the metastasis stage, cells in the blood stream are bathed in nutrients and therefore do not have a high demand on using OXPHOS, however downregulation of AKAP1 and the associated mitochondria fission and increased mitochondria biogenesis can better serve the needs of tissue invasion [56]. Future studies will be of interest in understanding the differential regulation of AKAP1 in cancer pathogenesis.…”

“…Decreased AKAP1 expression is implicated in glycolytic metabolism dependent migrating cells found in invasive populations of breast cancer cells. Lower AKAP1 should result in reduced mitochondrial fission, resulting in more efficient mitochondrial trafficking toward the edges of the invading cells [56]. On the other hand, increased AKAP1 expression is observed in tumors of end-stage cancer patients as well as in cisplatin chemotherapy resistance [57,58,60].…”