SIK2 Restricts Autophagic Flux To Support Triple-Negative Breast Cancer Survival

Abstract

c Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with multiple, distinct molecular subtypes that exhibit unique transcriptional programs and clinical progression trajectories. Despite knowledge of the molecular heterogeneity of the disease, most patients are limited to generic, indiscriminate treatment options: cytotoxic chemotherapy, surgery, and radiation. To identify new intervention targets in TNBC, we used large-scale, loss-of-function screening to identify molecular vulnerabilities among different oncogenomic backgrounds. This strategy returned salt inducible kinase 2 (SIK2) as essential for TNBC survival. Genetic or pharmacological inhibition of SIK2 leads to increased autophagic flux in both normal-immortalized and tumor-derived cell lines. However, this activity causes cell death selectively in breast cancer cells and is biased toward the claudinlow subtype. Depletion of ATG5, which is essential for autophagic vesicle formation, rescued the loss of viability following SIK2 inhibition. Importantly, we find that SIK2 is essential for TNBC tumor growth in vivo. Taken together, these findings indicate that claudin-low tumor cells rely on SIK2 to restrain maladaptive autophagic activation. Inhibition of SIK2 therefore presents itself as an intervention opportunity to reactivate this tumor suppressor mechanism. Breast cancer is an extremely heterogeneous disease that is classified by the presence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Cases where Ͻ1% of cells express ER, PR, or HER2 are considered triple-negative breast cancer (TNBC) (1). These molecular markers can serve as a critical stratification tool for tailoring effective therapies to sensitive patients. For example, antiestrogens such as tamoxifen are highly effective in ER-positive patients, and HER2-positive tumors are responsive to trastuzumab (2, 3). Conversely, TNBC tumors lack these targetable proteins, limiting first-line treatment to a combination of radiation and chemotherapy. This approach has changed little over the last 20 years and is characterized by high toxicity and frequent relapse of chemorefractory disease (4). Furthermore, levels of overall and disease-free survival in TNBC are significantly worse than those of other subgroups of breast cancer (5). Thus, for TNBC there is a dire need for less toxic therapies that target the major fulcrums supporting tumor cell survival.In addition to clinical and pathological markers, extensive gene expression profiling efforts by a number of groups have identified multiple intrinsic molecular subtypes within breast cancer. These subtypes include luminal A and B, which comprise the majority of ER-and PR-positive cases, as well a HER2-enriched clade. Importantly, this analysis has revealed substantial heterogeneity within TNBC. Broadly, TNBC can be subclassified into 2 intrinsic subtypes, basal like and claudin low, but up to 6 additional subclasses have been identified (6-9). Significantly, these groups can...

Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling

“…Hypertrophic chondrocytes and the bone major function of SIK3 is to serve as a protein kinase. Small-molecule SIK inhibitors have been studied as research tools and potential therapeutic agents for cancer (72)(73)(74)(75), inflammatory bowel disease (76), skin pigmentation (28), and osteoporosis (29). Our current in vivo results indicate that a major biologic action of SIKs is to mediate multiple biologic actions of PTH1R signaling.…”

SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways

“…Recently, SIK2 was associated with better survival in renal and liver cancer patients [ 35 ]. In contrast, SIK2 was proposed to support survival of TNBC cells with claudin-low subtype via limiting autophagic influx [ 33 ]. Since SIK2 was previously suggested as an important modulator of autophagosome maturation [ 27 ], its role in cancer cell survival through regulating autophagy requires further investigations.…”

“…Liu group indicated that overexpression of miR-203 sensitized Taxol resistant colorectal cancer cells via targeting SIK2 [ 32 ]. In another study, increased autophagic flux into TNBC cells was achieved by blocking of SIK2 [ 33 ]. Miranda and colleagues demonstrated that SIK2 contributes to ovarian tumor metastasis by localizing to the adipocyte rich environment to support survival and metabolic requirements of the cells [ 34 ].…”

Multistep regulation of autophagy by WNK1

“…To analyze its role in autophagy, WNK1 was knocked down with small interfering RNA (siRNA) in U2OS cells stably expressing green fluorescent proteintagged light chain 3 (GFP-LC3) (32,45). WNK1 depletion increased the number of GFP-LC3 puncta ( Fig.…”