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Abstract

BNIP3 is a mitochondrial protein that targets mitochondria for autophagosomal degradation or mitophagy. It is induced under physiological stresses such as hypoxia and nutrient starvation and functions to eliminate damaged mitochondria in order to maintain the overall mitochondrial integrity of the cell. BNIP3 is a bona fide HIF-1 target and is also regulated by RAS, pRB/E2F, p53, NFκB and FoxO3. While BNIP3 is up-regulated at pre-malignant stages of various human cancers including DCIS and PanINs, it is down-regulated by deletion or promoter hypermethylation in invasive breast cancer, PDAC, hematological malignancies, hepatocellular carcinoma, gastric and lung cancer, thus indicating that loss of BNIP3 may be critical to disease progression. However, while the role of BNIP3 in mitophagy has been well characterized, its function in tumor initiation and progression is not well understood. In order to assess the function and mechanism of BNip3 in tumor growth and progression to metastasis, we crossed BNip3 null mice to MMTV-PyMT mouse model of mammary tumorigenesis and the PDX1-Cre;LSL-KRASG12D mouse model of pancreatic tumorigenesis. Our results show that loss of BNip3 significantly promotes primary tumor growth and metastasis in both tumor models, demonstrating that BNip3 functions to suppress tumor progression to metastasis. BNip3 null mammary tumor cells exhibit significantly reduced mitophagy with a concomitant increase in dysfunctional mitochondria. While loss of BNip3 results in significant increase in mitochondrial mass, it reduces mitochondrial function and oxidative metabolism. However, BNip3 null mammary tumor cells show significantly elevated levels of glycolysis, indicating that defective mitochondria due to inefficient mitophagy can induce the Warburg effect. Notably, loss of BNip3 increases levels of ROS, which in turn promotes stabilization and activity of Hif-1α, thus demonstrating that BNip3 applies brakes on Hif-1α levels and activity in mammary tumor cells. We also show that BNip3 null mammary tumor cells rely on autophagy for survival, thus highlighting that effects of mitophagy inhibition are not the same as effects of inhibition of global autophagy. In the pancreatic tumor model, we show that loss of BNip3 increases primary tumor growth and reduces the latency to metastasis as well as overall survival. Using human pancreatic cancer cell lines, we also show that BNIP3 reduces cell growth, which is associated with reduced levels of c-Myc protein. However, the effect of BNIP3 on c-Myc is independent of its function of mitophagy. Overall, we have shown that BNip3 functions as tumor suppressor that inhibits progression to metastasis by mitophagy dependent and mitophagy independent pathways.

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