PINK1 對大腸癌的調控

Abstract

大腸癌長期位居國人十大癌症榜首，全球發生率與死亡率也位居前三名。過去發現粒線體異常會導致癌症的產生，也發現癌幹細胞具有特殊的粒線體特徵以及代謝方式，顯示粒線體在發展癌症療法上為良好的潛力標的。PINK1 是負責調控粒線體的重要蛋白，過去在不同癌症中發現 PINK1 異常可能導致癌症產生，然而 PINK1 對大腸癌及大腸癌幹細胞的影響以及機制仍不清楚。在本研究中，發現大腸癌細胞及癌幹細胞的 PINK1表現量分別有下降及上升的現象，接著分析 PINK1 基因削弱對細胞及粒線體造成的影響，發現 PINK1 會幫助細胞生長以及對抗低度的氧化壓力，並可能參與高氧化壓力下細胞凋亡的開啟。此外，削弱 PINK1 會透過抑制呼吸作用影響細胞在氧化壓力下的生長以及粒線體膜電位的維持，以及減少癌幹細胞的數量。因此，我證明了 PINK1 在大腸癌細胞的生長以及癌幹細胞的維持中扮演重要的角色，也發現改變代謝作用或施加適當的氧化壓力可能有助於抑制大腸癌細胞的生長以及清除大腸癌幹細胞。

Colorectal cancer is the most common cancer in Taiwan and is the one of leading causes of cancer-related death in the world. In the past decade, many studies found that defects in mitochondria may promote carcinogenesis. Several studies also showed that the state of mitochondria and metabolism is unique in cancer stem cell, indicating the potential to develop mitochondria-based cancer therapy. Serine/threonine kinase named PTEN-induced kinase-1 (PINK1) play important role in mitochondrial homeostasis. Several studies have found that abnormal PINK1 is associated to tumorigenesis. But whether PINK1 have direct impact on colon cancer is still unknown. In this study, PINK1 was found down-regulated and up-regulated in colon cancer cell and cancer stem cell, respectively. Knocking down (KD) PINK1 in colorectal cancer cell line HT29 decreased cell proliferation and impaired resistance to low-level oxidative stress, which might result from the impaired function of mitophagy and accumulation of mitochondrial ROS. After induced low-level oxidative stress by antimycin A, the survival rates and mitochondrial membrane potential of PINK1 KD cells were lower than control cell, while KD PINK1 inhibited apoptosis at high-level oxidative stress. Furthermore, I found KD PINK1 impaired stress resistance through inhibiting respiration ability. And the cancer stem cells significantly decreased in PINK1 KD HT29. Overall, these finding reveal the important role of PINK1 in progression and maintenance of colon cancer cells and cancer stem cells. Alteration of metabolism or proper oxidative stress may facilitate inhibition of cancer progression and clearance of cancer stem cells.